Immunology 6/14-6/18

Biologic actions of selected T cell cytokines:

***Learn the first 4

Summary of T cell Surface Molecules:

*See photo

Gamma/Delta T cells

-5-10% of total T lymphocytes -Appear earlier during development -Main T cell produced prior to birth and right at birth -Distribution: abundant in epithelial tissue -Limited diversity, recognize few structures -Function as cells in the innate immunity, respond to Ag directly followed by rapid production of cytokines, kill infected cells

Which one of the following statements about T cells involved in an immune response is NOT true?

-Activated T cells contribute to the activation of antigen presenting cells via CD40 ligand -Memory T cells generated during a primary immune response express high levels of IL-2 receptors and actively proliferate long after the primary response is completed (they do not actively proliferate, they dip back down)

B Cell Second Signals

-Activation of B cells is enhanced by a 2nd signal in addition to receptor signaling -3 main 2nd signals: 1. clustering of multiple IgM or IgD membrane receptors 2. complement-mediated co-stimulation 3. Toll like receptor signaling

B cell receptors (Ig) vs. T cell receptors (TCR)

-Affinity of an antibody is stronger - average affinity of Ig's increases during immune responses to protein antigens -Heavy chain class switching & change from membrane to secretory Ig -T cell receptors have no change of the affinity of antigen binding during immune responses

TLRs on B cells

-Also enhance the signaling of B cells -Still need microbe binding of B cell

Which one of the following statements about MHC-TCR interactions is NOT true?

-Antigen receptors on T cells bind to MHC molecules for only brief periods of time -The affinity of most TCR's for peptide-MHC complexes is similar to the affinity of antibodies for their antigens (The affinity of an antibody is WAY higher than that of T cells, so this is not true) -T cells usually require multiple engagements with an APC before a threshold of activation is reached

Subsets of B cell responses: T cell dependent vs. T cell independent

-B cells that are T cell dependent will interact with helper T cells, IgG, IgA, IgE -B cells that are T cell independent interact with lipids, polysaccharides, etc -> ONLY IgM, short lived, plasma cells

Co-stimulation and adhesion

-B7 / CD28 interaction is main secondary signal for naive T cell activation -LFA-1 / ICAM-1 main adhesion molecules (stabilizes interaction of APC/T cell so that activation may occur -CTLA-4 / PD1 are negative regulators

All of the following protein-protein interactions are involved in activation of naive helper T cells by antigen-presenting cells (APCs) EXCEPT:

-Binding of peptide-MHC complexes on the APC to the TCR on the T cell -Binding of CD4 on the T cell to nonpolymorphic regions of class II MHC molecule on the APC -Binding of integrins on the T cell with adhesion ligands on the APC -Binding of B7-2 on the APC with CD28 on the T cell -Binding of CD40L on the T cell with CD40 on the APC (this is after we have an ACTIVATED T CELL)

TCR-MHC molecule

-Binds to peptide, may only be a couple of amino acids long

Overview of B/T cell maturation

-Both T and B cells come from common lymphoid progenitor Proliferation: Failure to express preantigen receptor; cell death Pre-B/T antigen receptor expression: Pre-B/T cell expresses one chain of antigen receptor Antigen receptor expression Positive and negative selection

Symbiotic relationship

-CD4 & CD8 T cells function together in killing of microbes in macrophages

Activated CD4 T cell functions

-CD40 receptor is present on effector cells (macrophages, B cells, dendritic cells) -Cytokines produced by CD4 cells act as co-stimulators of effector cells

Recombination of H locus: Somatic recombination

-Catalyzed by VDJ recombinase expressed only in immature lymphocytes -Recombines DNA into a new set of material, heavy chain locus is broken down and permanently changed in that cell, D-J joining -happens BEFORE transcription occurs -Transcription occurs, produces mRNA -> RNA processing splicing -> Translation -Ultimately creates unique heavy chain per cell (heavy chain produced FIRST) -This occurs in immature B cells in the bone marrow

T cell receptors: structure

-Consist of 1 alpha chain and 1 beta chain -Contains one V region and one C region, both chains participate in the recognition of antigens (which for most T cells are peptides displayed by MHC molecules)

Effects of B Cell Receptor Activation

-Expression of proteins that promote survival -Antigen presentation -> interaction with helper T cells -Inc. expression of cytokine receptors -> responsiveness to cytokines -Inc. expression of chemokines -> migration from follicle to T cell zone -Generation of plasma cells -> Antibody secretion

Effector CD4 T Cells

-Follicular helper T cells remain in lymphoid organ, migrate into follicles ^^Help B cells to produce high-affinity antibodies -Effector T cells & antibodies enter circulation and go to sites of infection, elimination of microbes occurs

Process of recombination

-Generated by different combinations of V, D, and J gene segments -Introduces variability in the nucleotide sequences at the sites of recombination by adding/removing nucleotides -Result of this: development of a diverse repertoire of lymphocytes, in which clones of cells with different antigen specificity express receptors that differ in sequence and recognition

Isotype class switching

-Have to have activated B cell & activated T cell -HAVE to have CD40 ligand on Helper T cells and cytokines for class switching to occur -The cytokines from the helper T cells will designate which type of class switching will occur -IL-4 will produce IgE (fight helminths, primary way we get allergic reactions) -Cytokines produced in mucosal tissues will produce IgA (mucosal immunity, secreted across epithelial cells -> GI system, lungs, NO role in blood stream) -In the absence of CD40 ligand, cytokines, and and helper T cells we ONLY get IgM response and NO class switching

Production of complete antibody: Light chain locus

-Heavy chain recombination first -Separate chromosome creates the light chain from kappa or lamina locus -Somatic recombination V-J joining

Macrophage activation

-IFN-gamma from Th1 cells stimulates classic pathway and blocks alternate pathway (Inflammatory, granuloma's occur) -IL-13, IL-4 from Th2 cells stimulate alternate pathway and blocks classical pathway (anti-inflammatory effects)

Gene expression in T cell activation

-IL-2 is produced -CD69 (adaptive protein, keeps it in the lymph node to keep it there for full activation) -IL-2 receptor gets better/matures -CD40 ligand - used in activating other T cells -After all of these have been done, it will divide and make clones

Structure of lymphocyte receptor loci

-Ig H chains and TCR beta chain locus contain D segments -Diversity obtained from combinations of V-D-J or V-J segments -1 heavy chain gene, and 2 possible light chain genes -Heavy chain, light chain, loci are in 3 different places*** -Ig light chain encoded in TWO different areas -Heavy chain very similar to BETA chain, light chain very similar to ALPHA chain

Amplification in secondary response

-IgG are about 70% of plasma Ab -Higher avg affinity than IgM -Larger peak response

Human MHC locus

-MHC genes are co-dominantly expressed -MHC Class I - each locus contains three genes (designated HLA-A, HLA-B, HLA-C) MHC Class II - three gene sets per locus (HLA-DP, HLA-DQ, HLA-DR)

how do cyclosporine A, FK506 and Rapamycin work as immunosuppressants?

-Meds to avoid graft rejection These act on calcineurin, which is an activator of NFAT which increases IL-2 transcription

B Cell Receptor:

-Membrane bound antibodies (immunoglobulins) -Directly recognize native antigens or peptides -Bind to many different macromolecules -Exist in soluble form -Signal through Iga, IgB

T Cell Receptor:

-Membrane bound receptor, it CANNOT be secreted -Require presentation by MHC molcules -Bind only to peptide antigens -Membrane-bound only -Signal through CD3 and proteins

Direct B Cell activation

-Microbe directly binds to the antibody -Cross-linking of membrane IgAlpha and IgBeta -Involves NFAT as a transcription factor, same as T cell activation

Affinity maturation:

-Most antibodies produced in a primary immune response have a Kd in the range of 10−6 to 10−9 M, but with repeated stimulation (e.g., in a secondary immune response), the affinity increases to a Kd of 10−8 to 10−11 M. This increase in antigen-binding strength is called affinity maturation

Steps in T cell Activation / Differentiation

-Most of this interaction is occurring in dendritic cells in lymphoid tissue

What is X linked SCID?

-Mutations in the IL2RG gene cause X-linked SCID. The IL2RG gene provides instructions for making a protein that is critical for normal immune system function. -Boys with X-linked SCID are prone to recurrent and persistent infections because they lack the necessary immune cells to fight off certain bacteria, viruses, and fungi.

Overview of humoral activation

-Naive IgM, IgD B cell waiting for a microbe to come to it, can bind to entire protein, sugar, the microbe itself, etc -Just the binding alone of the microbe to the surface will activate the B cell to start proliferating, differentiating -Aid of helper T cells so it knows what type of antibody to produce -1st Ab produced from any infection results in IgM antibody secretion -> Isotype switching (can change to IgG, etc) -> Affinity maturation -> Memory B cell

T cells over time

-Naive T cells are very high in younger years until about 30, then they decrease as thymus is no longer putting out naive T cells -Memory T cells continue to increase as we age

Affinity maturation

-Occurs in germinal centers of follicles after activation by T cells -Strongest affinity with antigen selects clonal line for survival -Make point mutations (permanent) in the V chains (variability chain) to produce stronger Ab

Epitopes:

-Part of antigen recognized by antibodies: Linear epitopes - sequence related Conformational epitopes - based on shape of antigen

Maturation of T cell to CD4 or CD8

-Positive selection based upon weak affinity: Results in CD8 or CD4 single positive mature T cell -No receptor editing as in B cells Weak recognition of class II MHC + peptide = positive selection for mature CD4 T cell Weak recognition of Class I MHC + peptide = positive selection for mature CD8 T cell NO recognition of MHC + peptide = apoptosis STRONG recognition of either class I or class II = self antigen, negative selection (apoptosis)

T Cell Receptor Recombination

-Process same as for antibody recombination -TCR-beta similar to H chain, recombines first (contains D segment) -TCR-alpha similar to L chain

Function of Th1 Cells:

-Role in ingestion and killing of extracellular microbes -IFN-gamma stimulates expression of co-activator B7 on APCs -Th1 cells also responsible for increasing CD8 CTL activity through IL-2 secretion -Classical macrophage activation (enhanced microbial killing)

Characteristics of Memory T Cells

-Signals to drive their production are not clear -Requires IL-7 and other cytokines to stay alive -Do not produce cytokines or kill infected cells until encounter antigen again -A lot of our memory T cells reside in lymph nodes & respond quickly to second infection

Complement mediated activation (alternate pathway) B Cells

-Some of that complement stays on the microbe -B cell binds the microbe with the complement receptor, thus enhanced signaling of the B cell (CR2 complement signal)

How are T cell receptors and B cell receptors different?

-T cell receptors are just dimers -B cells have heavy chains and light chains -T cell receptors have only ONE binding site -Once a clone is made, that it is the T cell receptor for that cell. No class switching.

B Cell Receptor Signaling

-The antibody itself does not have ability to signal -Increase in transcription factors -Increase in production of specific proteins -All first put a IgM on their surface -Interaction happens DIRECTLY with the target, initially produces IgM, then needs an interaction with T cells to differentiate into IgA, IgB, etc. -IgAlpha and IgBeta sitting on the surface that bind to microbes

Antigen recognition by the T cell receptor (TCR):

-Triggers signals delivered to interior of the cells by molecules associated with the TCR (CD3 and zeta chains) and by the co-receptors CD4 and CD8, which recognize class II and I MHC molecules respectively

Secondary response

-Usually 1-3 days -Much higher antibody response -Relative increase in IgG (more predominant), along with sometimes IgA and IgE (heavy chain isotype switching) -High affinity

Primary response

-Usually 5-10 days -first time the immune system combats a particular foreign substance -Usually IgM>IgG -Lower avg. affinity, more variable

T cell independent B cell activation

-binds B-cells withOUT helper T-cell help -produces IgM -NO class switching -weak response -no memory -low-affinity antibodies -short lived plasma cells -marginal-zone B cells and B-1 cells: express antigen receptors of limited diversity & make predominantly T-independent IgM responses

Herpex simplex virus

-inhibition of an antigen presentation: HSV peptide interferes with TAP transporter

αβ T cells: Natural killer T cells and MAIT cells

-less than 5% of all T cells express αβ TCRs -called natural killer T cells (NK-T cells). -NK-T cells express αβ TCRs with limited diversity, and they recognize lipid antigens displayed by nonpolymorphic class I MHC-like molecules called CD1. -mucosal associated invariant T (MAIT) cells also express αβ TCRs with limited diversity, some of which are specific for bacterially derived vitamin B metabolites bound to an MHC-like protein called MR1. MAIT cells account for only about 5% of blood T cells, but up to 20%-40% of human liver T cells. The physiologic functions of NK-T cells and MAIT cells also are not well understood.

T cell dependent B cell activation

-needs T-cell help, will bind helper T cells to MHC II -memory response -class switching -high affinity antibodies -long lived plasma cells -follicular B cells -tend to be more involved in viral infections

Overview of cell mediated immunity

1. Activation of T cells by dendritic cells (mature dendritic cell can activate BOTH types of T cells at once) 2. Actions of activated T cells

Mechanism of CTL (CD8 cell) killing

1. Antigen recognition & binding of CTL to target cell 2. CTL activation and granule exocytosis 3. Apoptosis of target cell * Perforin facilitates entry of granzymes into the cytosol, granzymes activate apoptosis

Overview of adaptive immune response

1. Antigen recognition 2. Lymphocyte activation (clonal expansion) 3. Antigen elimination 4. Contraction (homeostasis) 5. Memory

Steps in T cell Mediated Activation of B cells

1. CD4 helper T cells and B cells are independently activated by antigen 2. T and B cells migrate towards each other and interact outside the follicle 3. Activated B cells present antigen to activated T helper cells leading to antibody secretion and initial isotype switching (heavy chain switching) 4. Activated B & T cells migrate back into follicle. Helper T cell becomes follicular helper T cells. 5. Antibodies undergo affinity maturation, further clonal selcetion, & development of memory B cells.

Steps in B cell maturation

1. Heavy chain recombination -Pro-B cell to Pre-B cell -Express heavy chain with light chains to get it to the surface (Checkpoint 1: signal through IgAlpha/IgBeta - expansion of clone ; No heavy chain expressed = apoptosis) -Turn off recombination at other allele -IgM and IgD secreted by mature B cells 2. Light chain recombination -Pre-B cell to immature B cell -Kappa first then lamina if no light chain produced (checkpoint 2: intact IgM signals through IgAlpha/IgBeta - expansion of clone ; No light chain = apoptosis) -Turn off recombinase enzyme 3. Co-expression of IgD -immature B cell to mature B cell -Recombined heavy chain may be spliced -Usually occurs after leaving the bone marrow 4. Negative selection -High affinity binding to self-antigen leads to receptor editing (light chain recombination) -High affinity binding may lead to apoptosis

THREE signals required for T cell activation

1. Recognition of MHC-Associated Peptides by TCR -MHC class I to CD8 T cell (intracellular) -MHC class II to CD4 T cell (extracellular) 2. Co-stimulation - B7 binding to CD 28 on T cells 3. Cytokines amplify the response: IL-2, IL-12, IL-14 -Depends on T cell population

Responses of T lymphocytes consist of sequential phases:

1. Recognition of cell-associated microbes by naive T cells 2. Expansion of the antigen-specific clones by proliferation 3. Differentiation of some of the progeny into effector cells & memory cells

First steps in T cell maturation:

1. TCR-beta recombination -Expressed with pre-T-alpha (helps get it to the surface) -checkpoint 1 2. TCR-alpha recombination -Signaling gives expression of CD4 and CD8 (double positive, doesn't know which type it will be yet) -checkpoint 2

Clonal expansion of T cells

100 cells at beginning of infection -over course of a week, it will jump to 10,000 -CD4 cells HELP other cells work, do not need as many, there will still be a substantial amount after infection to remember the infection and be able to respond next time -CD8 cells are the ones killing things, so there are much more of these cells

The core structure of antibodies:

2 identical heavy chains, 2 identical light chains - forms a disulfide-linked complex -each chain consists of a variable V region, which is the portion that recognizes antigen -A constant C region, which provides structural stability & performs the effector functions of antibodies in heavy chains -The V region of 1 heavy chain and 1 light chain together form the antigen-binding site, thus the core structure has 2 identical antigen-binding sites, can bind to TWO antigens at the same time

Types of cell mediated immunity:

2 types of cell-mediated immune reactions designed to eliminate different types of intracellular microbes: -CD4+ helper T cells activate phagocytes to destroy microbes residing in the vesicles of these phagocytes -CD8+ Cytotoxic T lymphocytes (CTLs) kill any cell containing microbes or microbial proteins in the cytoplasm, therby eliminating the reservoir of infection

T cell mediated immunity targets

A) Phagocyte - phagocytosed microbes that survive within phagolysosomes - microbes that escape from phagolysosomes into cytoplasm B) Nonphagocytic cell (eg. epithelial cell) - cellular receptor for virus - All viruses, all rickettsiae

What causes autosomal hyper-IgM syndrome?

AID mutation gives autosomal hyper-IgM syndrome - defect in activation induced deaminase results in no production of IgG, accumulation of IgM

CD40L-CD40 interaction

Activated T cells express CD40 ligand (CD40L) which binds CD40 on APCs. This interaction does not directly enhance T cell activation but improves the ability of APCs to stimulate T cells.

T cell Activation of B cells

Activated helper T cell expresses CD40L, secretes cytokines -> B cells are activated by CD40 engagement, cytokines -> B cell proliferation & differentiation

What causes dendritic cell maturation?

Activation by toll-like receptor, they mature on the way to the lymph nodes

Co-stimulation is required: Dendritic cell must be active

Activation of APC's by microbes, innate immune response is REQUIRED for a T cell response -Activated APC increases expression of costimulators, secretion of cytokines

Acute infection, memory T cells

Acute infection: ex. influenza, covid, etc -Quick viral load of effector T cells then over time transition to memory T cells

How do T cells get to site of infection?

Adhesion molecules: LFA-1

What is allelic exclusion and what is an example?

Allelic exclusion is a process by which only one allele of a gene is expressed while the other allele is silenced. This phenomenon is most notable for playing a role in the development of B lymphocytes, where allelic exclusion allows for each mature B lymphocyte to express only one type of immunoglobulin.

In the adaptive immune system, the molecules responsible for specific recognition of antigens are _____ and _____.

Antibodies... T cell antigen receptors

T Cell Receptor

Antigen receptors on a T cell. Unlike antibodies, T cell receptors are never produced in a secreted form. -Consists of 1 alpha and 1 beta chain -Each chain contains one V region and one C region

What is avidity?

Avidity gives a measure of the overall strength of an antibody-antigen complex. IgM has more bonds - Higher affinity IgG - stronger so IgG has more Avidity

B cell/T cell interaction

B cell recognition of native protein antigen -> receptor-mediated endocytosis of antigen -> antigen processing and presentation (class II MHC-peptide complex) -> T cell recognition of antigen

What is the primary target cell of Tfh?

B cells - antibody production

The interaction between a dendritic cell and a CD4 helper cell requires what molecules?

B7 on the DC and CD28 on the T Helper cell

Macrophage activation by Th1

Binding of CD40L to CD40 on macrophages functions together with IFN-γ binding to its receptor on the same macrophages to trigger biochemical signaling pathways that lead to the generation of reactive oxygen species (ROS) and nitric oxide (NO) and activation of lysosomal proteases. All these molecules are potent destroyers of microbes. The net result of CD40-mediated and IFN-γ-mediated activation is that macrophages become strongly microbicidal and can destroy most ingested microbes.

Effect of adhesion molecules on binding of T cells

Binding of T cells to APCs is enhanced by adhesion molecules, notably the integrins

Cross Reaction:

Binding of two distinct antibodies to structurally similar epitopes

In the class I MHC pathway of antigen presentation, peptides generated in the cytosol are translocated into the endoplasmic reticulum in which of the following ways?

By ATP-dependent transport via the transporter associated with antigen-processing (TAP) 1/2 pump

What are the cells that usually provide the co-stimulatory signals (B7) to NAIVE T cells?

CD28

Interaction of CD4 and IL-2

CD4 makes a much larger amount of IL-2 than CD8 cells do.

Production of diversity: happening in the maturation of B & T cells

Combinatorial diversity: limited by number of V, D, and J gene segments, -3x10^6 is number of possible antibodies Junctional diversity: (Removal of nucleotides/addition of nucleotides) is more robust, 10^11 possible repertoire with JD VDJ or VJ site encodes the CDR 3 loop (site of greatest diversity, site of antigen recognition)

Structure of lymph nodes

Dendritic cell comes to the T cell in lymph node and activates it -> bacteria and viruses can also move into the lymph nodes and interact with a naive B cell -Activate separetely, then come together & interact

Cross presentation to CD8 cells

Dendritic cells that phagocytose an infected cell then present on MHC I and MHC II molecules at the surface

Key points:

Diversity in antibodies and T cell receptors occurs through somatic recombination -Maturation of B/T cells occurs in a sequential manner with selection to ensure production of viable receptors that do not bind self antigens

What is the primary target cell of Th2?

Eosinophils

Classes of Antibodies

Every single antibody starts out at IgM, then C region of heavy chain changes. -Antibody keeps same affinity but changes function -IgG make up 70% of antibodies found in the plasma concentration/blood stream

T or F: Dendritic cells that enter lymph nodes through draining lymphatics migrate to the B cell-rich follicles in response to chemokines

False, they go to T cell areas

Completion of B cell maturation

Further maturation occurs after the immature B cells leave the bone marrow and enter the spleen. The final maturation step involves coexpression of IgD with IgM; this occurs because in any given B cell, the recombined heavy-chain VDJ unit may be spliced either to Cμ or Cδ exons in the primary RNA transcript, giving rise to μ or δ mRNA, respectively. We know that the ability of B cells to respond to antigens develops together with the coexpression of IgM and IgD, but why both classes of receptor are needed is not known. The IgM+IgD+ cell is the mature B cell, able to respond to antigen in peripheral lymphoid tissues.

Germinal Center

Helper T cell & B cell return to the follicle & go into the germinal center - this is where the B cell prolferates & makes a ton of B cells -Interacting with follicular dendritic cells, T helper follicular cells -Exit of high-affinity antibody-secreting cells & memory B cells

Application in determining immunity vs. infection: Hep A

Hepatitis A: -IgM elevated with NO IgG - Acute infection -IgG elevated with low/absent IgM - previous infection or immunity

What is the signature cytokine of Th1 cells?

IFN-gamma

What cytokine is produced by Th1 cells? What class does this switch B cells to?

IFN-gamma and lead to IgG switching

Effect of IFN-gamma on Th1 development

IFN-γ not only activates macrophages to kill ingested microbes but also promotes more Th1 development and inhibits the development of Th2 and Th17 cells.

The survival and proliferation of activated T cells are driven by the growth factor ____.

IL-2

IL-2 Receptor Maturation

IL-2 starts out with a low affinity -After activation occurs, IL-2 starts getting secreted and starts affinity maturation of the molecule itself -Stronger affinity, 100 fold increase in interaction -If we do not have a good gamma chain of the IL-2 receptor, T cells will not become active/mature - X-LINKED SCID caused by mutation in gamma gene

Th2 Development

IL-4 activates the transcription factor Stat6 and antigen-induced signals in combination with IL-4 induce expression of a transcription factor GATA-3, which is required for Th2 differentiation. Analogous to Th1 cells, these transcription factors stimulate the expression of Th2 cytokines and proteins involved in cell migration and thus promote Th2 responses. IL-4 produced by Th2 cells enhances further Th2 differentiation, thus amplifying the Th2 response.

What cytokine is produced by Th2 cells? What class does this switch B cells to?

IL-4 and lead to IgE switching

What antibody class do you get when there are no signals from helper T cells?

IgM

Immature lymphocytes: negative selection

Immature lymphocytes that strongly recognize self antigens are negatively selected and prevent from completing maturation -eliminates cells with potential of reacting in harmful ways against self tissues

Maturation of lymphocytes

In B cells, the Ig gene segments undergo recombination as the cells mature in the bone marrow In T cells, the TCR gene segments undergo recombination during maturation in the thymus

TH1 development

In response to many bacteria (especially intracellular bacteria) and viruses, dendritic cells and macrophages produce IL-12, and natural killer (NK) cells produce IFN-γ. Therefore, when naive T cells recognize the antigens of these microbes, the T cells are also exposed to IL-12 and IFN-γ. Type I IFNs, produced in response to viral infections, also promote Th1 differentiation. IL-12 and IFN-γ activate the transcription factors Stat4 and Stat1, respectively, and antigen-induced signals in combination with the cytokines induce expression of a transcription factor called T-bet that is essential for Th1 development and function.

Define humoral immunity

Indirect immunity mediated by B cells / antibodies of B-cells or plasma cells

CD8 Cells

Infected cell with microbial antigens in cytoplasm -Killing of infected cells

Herpes Simplex Virus

Inhibition of antigen presentation; HSV peptide interferes with TAP transporter

Which one of the following descriptions of cytokine interleukin-2 is NOT true?

It is only involved in the proliferation of helper T cells and not CTLs -Thus, it IS involved in the proliferation of helper T cells AND cytotoxic T lymphocytes

Which one of the following cell types would be most potent at activating naive T cells?

Langerhans cells -Follicular dendritic cells are there to interact with B CELLS

Signals required for a naive B cell to become activated

Like T cells, B cells also require signals along with antigen recognition -Requires the bringing together (cross-linking) of 2 or more membrane Ig molecules -Cross-linking occurs when 2 or more antigen molecules bind to adjacent membrane Ig molecules of a B cell -Signals initiated by antigen receptor cross-linking are transduced by receptor associated proteins (Igalpha and Igbeta) to form the B cell receptor (BCR) complex. -When brought together by cross-linking, the tyrosines in the ITAMS of Igalpha and Igbeta are phosphorylated by tyrosine kinases. -Net result is the activation of transcription factors that switch on the expression of genes whose protein products are involved in B cell proliferation.

Does a high or a low Kd indicate an antibody with STRONG affinity?

Low Kd (goes from as high as 6.0 down to <0.03) - reason behind multiple doses of vaccine

Lymphocyte maturation: Check points

Lymphocytes are selected to survive at several check points; only cells with complete functional antigen receptors are preserved. -T lymphocytes are positively selected to recognize peptide antigens displayed by self MHC molecules & to ensure that the recognition of the appropriate type of MHC molecule matches the coreceptor preserved

What is HLA-DR?

MHC Class II cell surface receptor

What is difference between someone who can clear Hep B and someone who goes onto have a chronic Hep B infection?

MHC variability

Comparison of MHC/Lymphocyte receptors

MHC: -Diversity through polymorphisms -Individual has limited # of molecules: 3 MHC class I and 6-8 MHC class II -Each molecule has broad specificity for antigens -Each APC produces many different MHC molecules Lymphocyte Receptor: -Diversity through somatic recombination -Individual can produce 10^11-10^16 unique receptors -Each receptor very specific to antigen -Clonal production (each lymphocyte produces only 1 unique receptor)

What is the primary target cell of Th1?

Macrophages

What is the function of LFA-1 and ICAM-1?

Main adhesion molecules -stabilizes interaction of APC/T cell so that activation can occur

How would the adaptive immune system accomplish the task of "producing memory for faster response upon future encounter with the microbe"?

Method: Memory lymphocytes produced during initial infection

Maturation/selection of lymphocytes

Myeloid progenitor produces basophils, eosinophils, etc Lymphoid progenitor: produces B cells, T cells, and natural killer cells

Do activated or naive T cells require binding of B7-2 on the APC with CD28 on the T cell?

Naive

What are the two signals required for naive T cell activation?

Naive T cells leave the thymus and enter secondary lymphoid organs. In secondary lymphoid organs, naïve T cells are activated by mature dendritic cells. T cell activation requires 2 signals: TCR and costimulation. Lack of costimulation during T cell activation leads to anergy.

_____ migrate to peripheral lymphoid organs, mainly lymph nodes. Whereas many of the ____ generated in lymphoid organs are able to migrate to any site of infection.

Naive T cells.... Effector T cells

___ cells can recognize antigens but are not capable of effector functions

Naive cells

What is the primary target cell of Th17?

Neutrophils

What happens in the absensce of CD40 ligand?

No class switching can occur -X-linked (males affected) Hyper IgM syndrome will occur

Somatic recombination:

Performed by B cells -allows each B cell to form its own unique antibody genes. -This occurs in immature B cells in the bone marrow -The genes that are clipped out are permanently destroyed

What is the main criterion that determines whether a protein is processed and presented via the class I MHC pathway in an antigen-presenting cell (APC)?

Present in the cytosol of the APC

What is the primary function of MATURE dendritic cells?

Presenting antigens to T cells

Discern between a primary and secondary antibody response

Primary antibody response: generated during the first exposure to an antigen Secondary antibody response: Increased heavy-chain isotype switching & affinity maturation, because repeated stimulation by a protein antigen leads to an increase in the # & activity of T lymphocytes

Interferon-gamma produces which antibody class type? What cell does it come from?

Produces IgG, comes from Th1 cell

T cell independent activation

Produces ONLY IgM with no/minimal class switching -B cells react with lipids, polysaccharides, microbe, etc -> produces IgM (short-lived plasma cells) -Primary response to bacteria, fungi -This is why we often have to treat the same bacterial infections over and over, does not produce good memory cells

Activation of CD8 T cells

Produces large numbers of cytotoxic T cells and memory T cells, and produces small numbers of suppressor T cells. CD4 activation enhances CD8 activation

Heavy-chain isotype switching: Activation Induced Deaminase

Protein produced in B cell called Activation Induced Deaminase which clips the inbetween DNA sequences and will result in class switching - stop producing IgM & only produce IgG -AID mutation gives autosomal hyper-IgM syndrome

What are the 3 components of an immature B cell?

Rearranged VDJ (heavy gene locus), Rearranged VJ (light gene locus), and IgM protein

Major histocompatibility complex class I antigens are found on all human cells with the exception of what type of cells?

Red blood cells

Complementarity-determining regions (CDR's)

Regions of contact with antigens -The V region of immunoglobulin (Ig) and TCR molecules contain hypervariable segments, called CDR's

In a clinical trial of a new antiviral vaccine composed of a recombinant viral peptide and adjuvant, 4% of the healthy recipients did not show evidence of response to the immunization. Further investigation revealed that all the nonresponders expressed the same, single allelic variant of HLA-DR but all the responders were heterozygous for HLA-DR alleles. Which of the following is the most likely explanation for this finding?

Response to the vaccine requires T cell recognition of complexes of the viral peptide with HLA-DR, but the peptide cannot bind to the allelic variant of HLA-DR found in the nonresponders

Homeostasis

Return of the immune system to a steady state -Signals from CD28 and IL-2 diminish and cells undergo apoptosis

What are the effector molecules of humoral immunity?

Secreted antibodies. They are capable of neutralizing microbes & microbial toxins and eliminating them by various effector mechanisms.

Comparison of antibody/TCR

See photo*

Viral infection

See photo*

Bacterial infection

See photo* -Still need T cells to interact with macrophages to kill off the bacteria

Receptor complexes

See photo* BCR complex binding to entire protein/carb/lipid or even the virus/microbe itself TCR complex: only binds if MHC molecule is present, APC must present the antigen -Contains CD3 molecule and zeta protein

What results in the selection of high-affinity B cells?

Somatic mutations in Ig V genes

Affinity

Strength of antibody binding to an epitope -Kd - dissociation constant, lower = higher affinity

Subsets of CD4 T cells

Study chart***

_____ are membrane receptors and are not secreted

T cell receptors (TCRs)

Maturing dendritic cells that migrate to a lymph node from peripheral tissues end up mainly in:

T cell zones

T Cell Receptor Complex

T-cell receptor, CD3 complex, CD4 molecule (interacts with class II MHC, must be present for docking of MHC) plus ζ chains

Function of Th17 cells

Th17 cells develop in response to extracellular bacterial and fungal infections and induce inflammatory reactions that destroy these organisms. -Increase inflammatory response by recruiting more neutrophils to site of infection (enhance innate immunity reaction) -The major cytokines produced by Th17 cells are IL-17 and IL-22. -Increase barrier integrity -Stimulate production of antimicrobial peptides -Typically going after bacteria, extracellular fungi, and bring neutrophils to areas of infection

Function of Th2 Cells

Th2 cells are induced by parasitic worm infections and promote IgE-, mast cell- and eosinophil-mediated destruction of these parasites The signature cytokines of Th2 cells—IL-4, IL-5, and IL-13—function cooperatively in eradicating worm infections.

Once a B cell has processed and presented an antigen, what event must occur before it becomes activated and starts secreting specific antibody?

The B cell must differentiate into memory cells and plasma cells.

Pre-B Cells are defined by the presence of what?

The cells that successfully make functional heavy-chain gene rearrangements and synthesize the Ig heavy-chain μ protein are called pre-B cells. Pre-B cells are therefore defined by the presence of the Ig μ heavy-chain protein.

Th17 development

The development of Th17 cells from naive CD4+ cells is driven by cytokines secreted by dendritic cells (and macrophages) in response to fungi and extracellular bacteria. Recognition of fungal glycans and bacterial peptidoglycans and lipopeptides by innate immune receptors on dendritic cells stimulates the secretion of several innate proinflammatory cytokines, including IL-1, IL-6, and IL-23. IL-6 and IL-23 activate the transcription factor Stat3. Signals induced by these innate inflammatory cytokines and another cytokine called transforming growth factor β (TGF-β), in combination with TCR signals, induce the expression of the transcription factor RORγT. These transcription factors are required for Th17 differentiation.

immunological synapse

The point of contact between APCs and T cells that stabilizes the interaction to increase the odds of T cell activation

Balance of Th1 / Th2 determine response

The relative activation of Th1 and Th2 cells in response to an infectious microbe may determine the outcome of the infection -Ex. the protozoan parasite Leishmania major lives inside the phagocytic vesicles of macrophages, and its elimination requires the activation of the macrophages by L. major-specific Th1 cells. Most inbred strains of mice make an effective Th1 response to the parasite and are thus able to eradicate the infection. However, in some inbred mouse strains, the response to L. major is dominated by Th2 cells, and these mice succumb to the infection.

What is cross reactivity?

This refers to the tendency of one antibody to react with more than one antigen. EX: immunizing with cowpox (harmless) to vaccinate for small pox (harmful).

TCR signaling pathway

Transcription factor: NFAT: increases IL-2 / IL-2R transcription *Remember CD28 & B7 are both needed to co-stimulate -Cyclosporine A and Tacrolimus are meds to avoid rejection - act on calcineurin which is an activator of NFAT

How do we vaccinate against bacteria?

Trick body into producing a T cell dependent response rather than just T cell independent

T or F: IgG are about 70% of plasma antibodies

True

T or F: Immature dendritic cells are ubiquitously present in skin and mucosal tissues

True

T or F: The amounts of antibody produced in the primary immune response are smaller than the amounts produced in secondary responses

True

Does class switching require helper T cells?

Yes

Monoclonal antibodies

a collection of identical antibodies that interact with a single antigen site -Take advantage of this process for drugs

Define cell mediated immunity

an immune response that does not involve antibodies.

Main targets of cell-mediated immunity:

directed primarily at microbes that survive in phagocytes and microbes that infect non-phagocytic cells. It is most effective in removing virus-infected cells, but also participates in defending against fungi, protozoans, cancers, and intracellular bacteria.

Antigen-presenting cells (APCs):

display antigens using class II MHC.