wk3-L6-CD4+ T helper cells-Effector function of T cells(Th1 and Th2 helper cells)

CD4+ T cell antigen recognition

-CD4+ T cells recognise antigen using a TCR -antigen must be presented by an APC(antigen presenting cell)>not like B cells -Examples of APC: >DCs >macrophages >neutrophils -APC presents antigen to the T cell using the MHC

Immune response and CD4+-T cell differentiation

-During expansion into CD4+ >T cells develop 2 different form that are the same but have diff. functions depending on nature of antigen 1-Th1 2-Th2

Effect of Th1 and Th2 responses in the west

-In the west Th1 and Th2 responses also complicate ppls lives -Th2 responses→IL-4→IgE→allergies -Rhinitis Type 1 hypersensitivity=inappropriate Th2 (histamine) responses

Clonal expansion of CD4+ cells

-Naive T cells=small resting cells with condensed chromatin and scanty cytoplasm>synthesize little RNA/protein -Activation of naive T cells→re enter cell cycle + divide rapidly→produce a lrg # of progeny that will differentiate into effector T cells -proliferation and differentiation are driven by cytokine interleukin-2(IL-2)>produced by activated T cell itself

Immune response and CD4+ cells-Part 5

-Problem is cleared -Memory cells generated during clonal expansion in the primary immune response stay in the peripheral blood ready for infection by same pathogen again→more rapid secondary response initiated

Th0 cells differentiate into Th1 cells in presence of IL-12/IL-23

-decision for differentiation to Th1=IL-12/IL-23 1-TLR receptors recognize bacterial and viral products→antigen presented on dendritic cell 2-DC releases IL-12 and IL-23 3-CD4+ Th0 cell differentiates into CD4+ Th1 cell 4-Th1 cell secretes IFN-γ which stimulates DC→secretes IL-12 and IL-23→cycle starts again -Transcription factors involved: >Th1=T-bet >Th2=GATA-3

Immune response and CD4+ cells-Part 2

-immature T cells home from the Thymus and the B cells from the bone marrow into the lymph nodes -T cells wait for an immune response in the lymph node

Immune response and CD4+ cells-Part 1

-thymus and bone marrow=primary lymphoid organs>make lymphocytes -secondary lymphoid organs→produce immune response -tissue drains into lymphatic vessels→drain lymph nodes

CD4+ T helper cells are progressively lost in HIV infection-Sabin et al

-CD4 =receptor for HIV -AZT drug→resistance within weeks 1990s -follow infections from health care workers with needle stick injuries - gradual rise in virus and decrease in CD4+ cells -viral copy number decreased -Period of clinical latency: >virus kills CD4 in gut(don't have access) -When CD4>200ul→AIDs→onset of opportunistic infections→multiple infections→immunodeficiency and death

Th1 cells

-Function: >helps control bacteria that can set up intravesicular infections in macrophages e.g. myobacteria(leprosy and TB) >activate macriphages to kill microbes located within macrophages' phagosome >activate cytotoxic T cells to kill infected cells >may also stimulate B cells to secrete specific subclasses of IgG antibodies>coat EC microbes and activate complement pathway -secrete: interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) -scarring due to macrophages spewing gunk -embryonic stages b4 development of macrophages dont scar 1-Th1 cell recognizes bacterial antigens displayed on surface of infected macrophage 2-interact with infected to further activate it→stimulates macrophage microbial activity→kills its resident bacteria

Cytokines made by CD4+ T helper cells

-Interferon-gamma(IFN-γ): anti-viral, activates macrophages, increases MHC-II expression -Tumour necrosis factor-alpha(TNF-α): kills cancers, activates many other cell types -IL-2: T cell GF, activates macrophages -IL-3:Mast Cell GF -IL-4: B cell GF, induces IgE -IL-5: B cell GF, eosnophil GF -IL-10: B cell differentiation factor, immunosuppressive -TGF-β: switches classes of B cells to make IgA, immunosuppressive

What happens when B cells are activated by TCR binding?

-T cell help activated B cells become plasma cells which produce huge amounts of diverse antibody -all have same specificity for antigen

Isotype regulation by murine T cell cytokines

-T cell-derived cytokines control the class of antibodies made -certain cytokines either induce(green) or inhibit (pink) the production of certain antibody isotypes -inhibition mostly results from switch to the different istoype

How do T cells know to become Th1 or Th2 cells?

-T cells are flexible when they come out of the thymus=Th0 cells -cytokines turn Th0 cells into either Th1 or Th2 cells

Immune response and CD4+ cells-Part 4

-T cells that match MHC on APC→clonal expansion and proliferation -they are transported to the site of injury carry out their effector responses

Other subtypes of CD4+ effector T cells and their TFs

-Th17: >TF=RORγt >differentiation signal:TGFβ and IL-6/IL-12 >repressed by: IFN-γand IL-4 -iT-Reg: >TF=Foxp3 >differentiation signal:TGFβ >repressed by: IL-4

Cytokine produced by other subtypes of CD4+ effector T cells

-Th17→IL17 and IL-22 -iT-Reg(induced regulatory T cell)→TGFβ and other suppressive molecules

Summary of CD4+ effector T cell subtypes and their functions

-Th1: >cell mediated immunity >defence against IC pathogens -Th2: >humoral immunity >defence against parasitic worms→allergies -Th17: >defence against EC bacteria >autoimmunity -iT-Reg: >immunosuppression >autoimmunity, cancer

Populetions of Unconventional and conventional T cells

-Unconventional T cells are categorized into 2 major populations those that express NK cell markers(NK T cells) and those that don't express them (gamma delta T cells) -Populations of conventional and unconventional T cells : >90% of T cells in humans and mice peripheral blood and conventional lymphoid organs are conventional T cells >Only a minority are unconventional T cells <10% (gamma delta cells) New research: >95% of conventional T cells >Same # of conventional and unconventional T cells (some may same more but undiscovered) e.g. in the liver NK T cells account for up to 30% of total # of T cells in the liver only 2% of NKT cells in peripheral blood

Some bacteria are hard to kill e.g. TB

-bacteria can be taken up by macrophages in usual way but can evade killing mechanisms -99% are asymptomatic -difficult to kill due to waxy coat on bacteria 1-CD4+ Th1 cell releases IFN-γ and TNF-α which activates TB-infected macrophage 2-TB infected activated macrophage can't kill resident bacteria on its own 3-Immune system walls of infected macrophage and bacteria >if TNF-α is stopped the complex will burst and break open→has to be maintained daily by CD4+ T helper cells 4-Caseating granuloma=complex >looks like cheese under the microscope

Th0 cells differentiate into Th2 cells in presence of IL-4

-decision for differentiation to Th2=IL-4 -Th2 produces IL-4 >could come from mast cells→feedback loop >mast cells respond to warms

Activated CD4 T cells differentiate into several subsets of functionally different effector cells

-different effector cells have different functions -subsets defined on basis of different combinations of cytokines that they secrete -main functional classes: 1-Th1 2-Th2 3-Th17: help protect against EC bacteria and fungi by stimulating the neutrophil response that helps clear these pathogens >induced early in adaptive immune responses 4-Regulatory T cells: >found in periphery >function=to suppress T cell responses >involved in limiting the immune response and preventing autoimmune disease >2 main grps: natural regulatory T cells, induced regulatory T cells

2 manifestations of Leprosy

-discovered in Mill Hill lab -use armadillo to research leprosy(bacterial infection) 1-Tuberculoid Leprosy(Limited disease): >likely to live >Th1 is dominant response >Cytokine= IFN-γ >activated macrophages >low #s of organisms(bacteria) 2-Lepromatous Leprosy(disseminated/severe disease): >Th2 is dominant response >Cytokines: IL-4, IL-5, IL-13 >Hyperglobulinemia=too much antibodies >high numbers of organisms(bacteria) >damages nerves=more chance of death

Th2 cells

-function: >defend the animal against EC pathogens >help control infections by parasites, particularly helminths, through promoting responses mediated by eosinophils, mast cells and the IgE Ab isotype 1-can stimulate B cells to make most classes of antibodies(inc. IgE and some subclasses of IgG) 2-IgG antibodies bind to mast cells, basophils, and eosinophils→release local mediators that cause sneezing, coughing, or diarrhea>help expel EC microbes and larger parasites from epithelial surfaces of the body -required for switching of B cells→IgE Ab→fights parasite infections and is also involved in antibody response to allergies -secrete: interleukins 4, 5, 10, and 13 (IL-4, IL-5, IL-10, and IL-13) -Th2 differentiation is of additional medical interest

Naive CD4+ T helper cells

-gave a TCRαβ and CD4 >also have CD28(like CD8+ T cells) -TCRαβ= a T cell receptor→T cell -CD4+ T cells has 80,000 molecules of CD4 -only mature lymphocytes with CD4 -myeloid have little (macrophages) - CD4+→present and gene expressed

Classical IgE mediated allergy (Type I hypersensitivity)

-in developing countries Th2 responses are good→worm infections are more common -exposed to parasites→more tolerant immune systems -in developed western countries we have less worm and parasite infections→don't need much Th2 responses >inappropriate Th2 responses cause eczema and allergies

the concept of T-cell help

-linked recognition -T cell can help all B cells that can generate the same peptide as the DC 1-antigen is taken up by the DC 2-DC breaks it up + presents on MHC I+II 3-presents it to T cell(CD4+ Th2 cell) 4-B cell gets activated by binding and internalizes receptor with antigen→degrades the antigen and presents it at MHC 5-TCR on T cell recognizes peptide on B cell MHC-II

T cells develop in the thymus

-progenitor becomes a committed T cell once it enters the thymus -thymus induces tolerance to body proteins otherwise→autoimmune disease -2 types of T cells: 1-Conventional T cells: •CD4+ T helper cells(Th1 and Th2)-conductors •CD8+ T cells(cytotoxic killer T cells-CTLs)-power house of immune system 2-Unconventional T cells: don't behave like conventional •γδ-roles in protection against tumours in the gut •Intraepithelial lymphocytes(IELs)-found in gut, lung,skin •NKT cells-T cells that have features similar to NK cells

What do activated CD4+ T helper cells do?

-provide help -stimulate the production of antiviral antibodies by B cells and produce cytokines that enhance the immune response

T follicular helper cell(TFH)

-recently recognized class -specialized for providing help to B cells in the lymphoid follicles -TFH(not Th1/Th2 cells) =the effector T cell that mostly provides B cell help for high affinity antibody production in the lymphoid follicles -identified by their location and expression of certain markers(CXCR5 and ICOS) identified in both mice and humans -can secrete cytokines characteristic of either Th1 and Th2 cells >in the course of an infection B cells could receive help in a follicle to: 1-switch to IgE through presence of Th2 cytokines 2-switch to IgG2a through presence of Th1 cytokines -represent a distinct branch of effector T cells that remain in the lymphoid tissues and are specialized for providing B cell help

induced regulatory T cells

-recognized more recently -thought to differentiate from naive CD4 T cells in the periphery under the influence of particular environmental conditions -also called adaptive regulatory T cells

2 manifestations of Leishmaniasis

1-Cutaneous Leishmaniasis (orient boils) >limited disease>lives >Th1 is dominant response 2-Visceral Leishmaniasis(Kala-azar/black fever) >Th2 is dominant response >disseminated disease>lethal

2 manifestations of Tuberculosis

1-Lepromatous TB >Th1 dominant response >limited disease >caseating granulomas formed 2-Miliary TB >Th2 dominant response >looks like little seeds in the lungs >infection spreads quickly to brain→lethal >disseminated disease

CD4+ effector T cell subtypes control the type of resulting immune response

1-Th1 cells: -secrete 3 types of cytokines: IL-2,IFN-γ,TNF-α -results in cell mediated immunity: NK cells and killer T cells >for infected cell to kill the pathogen b4 new ones are released >IC bacterial infection and viruses 2-Th2 cells: -secrete 3 types of cytokines:IL-4,IL-5,IL-13 -resulting immune response=Humoral immunity >antibodies, complement, proteins

Autocrine growth pathway

1-combined actions of signal 1 and 2 stimulate the T cell to proliferate and begin to differentiate into an effector cell by an indirect mechanism 2-in culture>CD4 cells stimulate own proliferation and differentiation by inducing the cells to secrete a interleukin 2(cytokine-IL-2) 3-CD4 cells simultaneously synthesize high affinity cell surface receptors that bind it 4-IL-2 binds to the IL-2 receptors→activates IC signalling pathways→turn on genes that help T cells to proliferate into effector cells -Advantages of autocrine growth pathway: >Helps ensure that T cells differentiate into effector cells only when substantial # of them respond to antigen simultaneously in the same location e.g. lymph node during infection >Only then do IL-2 levels rise high enough to be effective

Activated T cells secrete and respond to IL-2

1-encounter with specific antigen in presence of co-stimulatory signal→T cell enters G1 phase of the cell cycle and induces synthesis of IL-2 and α chain of IL-2 receptor(CD25) >resting form of T cell expresses a form of the CD25 receptor with only β and γ chains→binds to IL-2 with moderate affinity→allows resting T cells to respond to high concentrations of IL-2 2-association of the α chain with the βγ heterodimer→receptor with a high affinity of IL-2→allows the cell to respond to low conc.s of IL-2 3-IL-2 binds to high affinity receptor→progression through cell cycle 4-T cells can divide up to 3x/day for several days→one cell can give rise to a clone of 1000s of cells that all have the same receptor for the antigen -IL2=survival factor for T helper cells>allows differentiation into effector T cells >removal of IL-2 from activated T cells→death

Immune response and CD4+ cells-Part 3

1-inflammation and swelling→bring liquid to site of damage from blood →brings cells e.g. macrophages and neutrophils →pressure to move lymph to lymph node 2-DCs move to lymph node and process antigen to put it on the MHC→present it to the helper T cell