Immunology Final Exam (Part 1: Lecture 25, 26)
Stress Molecules
Can be recognized by gamma delta T cells and that fill critical gaps in host defense; respond by proliferating and differentiating into gamma delta Th and gamma delta CTL effectors
What makes a T cell double negative?
Carries homodimeric CD8alpha alpha co receptors or no co receptor
What is the primary function of NK cells?
Non-specifically kill tumor or virally-infected cells secrete cytokines
Explain recognition of target cells by NK cells
Not MHC restricted some cases show similar NK-cell activity with syngeneic and allogeneic tumors
Gamma delta TCRs interact with ligands similar to ligand recognition by
Pattern Recognition Receptors (PRRs)
NK cell tolerance
Self tolerant
What happens to a patient when they have complete absence of NK cells
Serious varicella virus (chickenpox) & cytomegalovirus infection
Explain Stress molecules sizes
Small pyrophosphate-like molecules Peptides or whole proteins (heat shock proteins (HSPs))
gamma delta T cells Ag Recognition
Specific to stress molecules such as injury infection or cancerous transformation may be regulated more like that of NK cells
Natural killer group 2 (NKG2) & Killer Ig-like receptor (KIR) class include
both activating & inhibitory members
NKT cells immediately __________
commence cytokine secretion (rapid response & first line of defense)
NK cells are involved in
early response to infection with certain viruses & intracellular bacteria and are the first line of defense against virus infection
When gamma delta T cells are activated by Ag they generate ______
effectors in a manner similar to alpah beta T cells even thoguh the signaling pathways linking TCR stimulation to new transcriptions are slightly different
What is the first wave of T cells produced in humans or mice?
gamma delta T cells (provide immune defense in fetus and neonates before adaptive immunity)
Natural killer (NK) cells are what kind of cells?
non-phagocytic lymphoid cells that possess cytoplasmic granules
Activated NK cells DO NOT
proliferate & differentiate (responds within hours of infection)
gamma delta are a major population in what species
ruminants (cows and sheep) & pigs
Gamma delta T cells are interspersed among ____ leading to them being the first defenders
the epithelial cells (SALT) and mucosae (MALT)
NK cell receptors are generally _______ proteins
transmembrane
Define Natural cytotoxicity
"Missing self"; contain perforin & granzymes that induce apoptosis in target cells; have preformed granules
In humans what are the majority of T cells?
CD4+ CD8+ and alpha beta T cells
NKT cell receptors
- 'semi-variant' TCR alpha beta (TCRalpha chain is essentially invariant) - Invariant or iNKT cells - CD3 complex - CD4+CD8-, CD4-CD8+ or CD4-CD8-
What do the TCRs of NKT cells recognize?
- Glycolipid - Glycosphingolipid - Lipids presented on non-polymorphic CD1d molecules
NKT cell antigens
- Glycolipids - Microbes that contain CD1d-restricted glycolipid Ags - Microbes that do not contain such glycolipid Ags can still activate NKT cells (via indirect routes)
Cytokines produced by gamma delta Th effectors
- activate NK cells and macrophages - support differentiation of activated alpha beta Th0 cells - influence isotype switching in B cells - influence leukocyte trafficking and wound healing
Define NK activating receptors in natural cytotoxicity
-Triggered by ligands either constitutively expressed on healthy cells or may be induced or up regulated in response to viral infection, malignant transformation (tumor) or other stresses -Non-classical NHC molecules
What is a bridge for innate adaptive immunity?
Natural Killer cells, gamma delta T cells and NKT cells
What are two factors that contribute to the intensity of NK cell response in natural cytotoxicity?
1. How many inhibitory versus activatory receptors are engaged 2. Affinity of those receptors for their ligands
What are two surface receptors that help trigger NK-mediated natural cytotoxicity
1. NK activating receptors 2. NK inhibitory receptors
What are two examples that non-peptide Ags are also presented by
1. non-classical Class Ib molecules 2. non-polymorphic CD1
What percentage of NK cells are in the peripheral blood cells?
10-15%
What is the lifespan of a NK cell?
7-10 days
In sites of inflammation ____ may help to activate gamma delta T cells
APCs
Natural cytotoxicity receptor (NCR) class contains only _______
Activating receptors
What immune system is NKT cells a member of?
Adaptive immune system and exhibit some characteristics of cells in the innate immune system
Natural killer (NK) gamma delta T cells and NKT cells are part of what immunity reaction?
Adaptive immunity
Gamma delta T cells serve as what to alpha bata T cells
Antigen presenting cells (APCs)
What can Cytolysis be induced by?
Natural cytotoxicity, ADCC or cytotoxic cytokines
Define NK inhibitory receptors in natural cytotoxicity
Bind only to classical MHC class I molecules
Where do NK cell originate from?
Bone marrow-derived hematopoietic precursors
gamma delta T cells can be activated with phosphorylated metabolites without
CD28 or CD40 mediated costimulation
NK cells that survive infection show
Characteristics of memory lymphocytes
gamma delta T cells in peripheral tissues
Conventional CD28-mediated costimulation
Gamma delta T cells in epidermal & intestinal
Costimulated when other surface receptors are engaged by stress ligands
What is promoted when NK cell and DCs interact?
DC maturation & efficient induction of Th & CTL responses
Define "induced self"
Elevated amounts of ALs which results in abnormal host cell to be killed
Explain the importance of the balance between activating & inhibitory signals in natural cytotoxicity
NK cells are able to distinguish healthy cells from infected cancerous or abnormal cells (opposing-signals model)
Where are NK cells found?
High frequency in spleen, liver, uterus & peripheral blood and more moderate numbers in bone marrow, lymph nodes and peritoneum
Phagocytes & innate leukocytes produce what cytokines upon activation
IFN alpha/beta, IL-12, IL-15, TNF (Prime NK cells and induce them to synthesize IFN-gamma)
NK activity is stimulated by what cytokines
IFN-alpha, IFN-beta, IL-12
What cytokines are required to activate resting NK cells?
IFN-alpha, IFN-beta, IL-12 or IL-15 present in a site of infection and induce up regulation of many activating & inhibitory receptors and adhesion molecules (no effector differentiation)
What chemokines, growth factors, and cytokines are present in the activation of primed NK cells by FCgamaRIIA?
IFN-gamma, TNF (can mediate cytotoxicity), IL-1, IL-3, & IL-6 (these play an important role in both innate & adaptive immunity
NKT cells may not be activated unless what receptors are engaged?
IL-12/IL-18 or IFNalpha/beta
What drives immature NKT cells to maturation?
IL-15
Explain in general Ag recognition
Respond to a wide variety of bacterial protozoan & viral molecules & products (Some specific to certain type of determinants that can counter whole group of pathogens)
Activatory receptors signal through associated
ITAMs
Inhibitory receptors signal through associated
ITIMs
Explain of NKT cells are developed
In the Thymus from NK/T precursors and follow the alpha beta T cell developmental pathway diverge from them during the DP stage
Explain 'Experienced NK cells'
Increase their longevity & second time infection can proliferate & exhibit enhanced cytolytic & cytokine secretion capabilities
Explain placenta and NK cell receptors
Induce maternal uterine NK cells to secrete cytokines to help ensure a successful pregnancy
IFN-gamma
Influence the innate immunity by activation of macrophages and enhance TH1 cell development
What makes NK cells different from NKT, B & T cells
Lack of TCRs or BCRs expression and have TCR or BCR genes in germline configuration
Infected & cancerous cells frequently downregulate their _____
MHC class I
Gamma delta T cells DO NOT require involvement of
MHC or processing & presentation of peptide Ags by APCs (respond to a broad range of pathogens or abnormal cells)
What is not a feature of gamma delta T cells?
Memory
Explain missing self
Missing normal levels of MHC class I on healthy cells therefore kill the target cells
What are two surface expressions NK cells show?
NCAM; CD56 FC gamma RIIIA (CD16)
What are NKT cells effector functions?
Prominent in induced innate immunity and immediately carry out their effector functions by activating cytokine and chemokine secretion
What are examples of TCR gamma delta ligands?
Proteins or peptides, non-protein Ags, and lipids & phosphorylated nucleotides (Soluble or bound to cell surface)
Define induced innate response
Rapid & involve broad recognition of Ag independent of classical pMHC
NK cells can be __________ when an infection & inflammation is present in almost any tissue in the body.
Rapidly recruited
Explain the development of gamma delta T cells
Rearrangement of TCRgamma delta genes is detected in thymocytes by 8 weeks in human fetus; and under the influence of fetal thymic stromal cells distinct waves of gamma delta T cells populate specific organs
What do NK cells cytokines directly regulate?
T & B cells functions & differentiation
Explain NKT cells
T lineage cells that have characteristics common to CTL & NK cells and found virtually everywhere T and NK cells are found
What are gamma delta T cells composed of?
TCR gamma, TCR delta, and CD3 complex
Cytokines produced by NKT cells have powerful effects on ________
alpha beta T cells differentiation and function (adaptive defense)
Explain what the engagement of FCgammaRIIIA (CD16) and NK cells causes
The release of cytotoxic granules
Killing by natural cytotoxicity also results when
There is normal level off self MHC class I but abnormally high levels of activating ligands (ALs)
Explain why TCRs lack the fine antigenic specificity
They bind directly to non-peptide antigens without the need for presentation by another molecule
What is a secondary source of NK cells?
Thymus (generate a subset of thymic NK cells)
Where do gamma delta cells develop?
Thymus from NK/T precursor (positive & negative thymic selections & peripheral tolerance occurs)
Explain NK-mediated ADCC
Triggered by binding to IgG molecules and have engaged epitopes on tumor cells or virus infected cells
In the secondary lymphoid tissues and thymus there are _______ numbers of gamma delta T cells
Very low
NK cells control
Viral replication during the time required for activation, proliferation & differentiation of CTL-p cells into effector CTLs
When is the Antimicrobial compound nitric oxide (NO) produced?
When activated gamma delta T cells induce neighboring epithelial cells
How are NK/T precursors generated?
When common lymphoid progenitors (CLPs) that remain in the bone marrow
When is keratinocyte growth factor (KGF) secreted and what is its function?
When gamma delta T cells in the skin are activated and stimulates growth and differentiation of skin epithelial cells
Gamma delta T cells express
a dominant or 'canonical' TCR containing specific V gene segments (Human intestines: Vgamma1 Vdelta2 TCRs) (Human Skin and peripheral blood: Vgamma9 Vdelta 2 TCRs)
Single Stress Af in response to
a variety of infections/injuries and monitor a variety of assaults
Natural killer (NK) gamma delta T cells and NKT cells have an influence on what two cells?
alpha beta T cell and B cells