Chapter 5 – t cell–mediated immunity lecture 5

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Chapter 5 – T Cell–Mediated Immunity

Dr. Hafez Sumairi

Learning outcomes

1.What signals are needed to activate T lymphocytes,and what cellular receptors are used to sense andrespond to these signals?

2.How are the few naive T cells specific for any microbeconverted into the large number of effector T cells thathave specialized functions and the ability to eliminatediverse microbes?

3.What molecules are produced by T lymphocytes thatmediate their communications with other cells, such asmacrophages, B lymphocytes, and other leukocytes?

Cell-mediatedimmunity (CMI)

Phases of T cellresponsesNaive T lymphocytesrecognize antigens in theperipheral lymphoid organs,which stimulates theirproliferation anddifferentiation into effectorand memory cells, and theeffector cells are activated bythe same antigens inperipheral tissues or lymphoidorgan

Phases of T cellresponsesThe responses of naive Tlymphocytes to cell-associated microbialantigens consist of aseries of sequential stepsthat result in an increasein the number of antigenspecific T cells and theconversion of naïve Tcells to effector andmemory cells

Antigen recognition and co-stimulation

Antigen recognition andco-stimulation• CD4 or CD8, both of which are called co-

receptors because they function with the TCRto bind MHC molecules

• TCR complex are TCR, CD3, and ζ chain

• Although the α and β TCRs must vary amongT cell clones to recognize diverse antigens, thesignaling functions of TCRs are the same in allclones, and therefore the CD3 and ζ proteinsare invariant among different T cells.

• Polyclonal activators of T cells include certainmicrobial proteins called superantigens.

Role of adhesion molecules in T cellresponses• Adhesion molecules on T cells recognize their ligands on APCs and

stabilize the binding of the T cells to the APCs

• The major T cell integrin involved in binding to APCs is leukocytefunction–associated antigen 1 (LFA-1), whose ligand on APCs iscalled intercellular adhesion molecule 1 (ICAM-1)

Role of co-stimulation in T cellactivation• The full activation of T cells depends on

the recognition of co-stimulators on APCsin addition to antigen

• B7-1 (CD80) and B7-2 (CD86), both ofwhich are expressed on APCs and whoseexpression is increased when the APCsencounter microbes, are ligands for CD28Co-stimulators for T cells.

• Adjuvants function mainly by inducingthe expression of co-stimulators on APCsand by stimulating the APCs to secretecytokines that activate T cells.

• Proteins homologous to CD28 also arecritical for limiting and terminatingimmune responses

• CTLA-4 and PD-1 are induced inactivated T cells

Stimuli for activation of CD8+ T cells• The activation of CD8+

T cells is stimulated byrecognition of class IMHC–associatedpeptides and requirescostimulation and/orhelper T cells

• APCs, principallydendritic cells, mayingest infected cells andpresent microbialantigens to CD8+ Tcells (cross-presentation) and toCD4+ helper T cells.

Biochemicalpathwaysof T cell activation• On recognition of antigens

and costimulators, T cellsexpress proteins that areinvolved in proliferation,differentiation, and effectorfunctions of the cells

Biochemicalpathwaysof T cell activation• The biochemical pathways

that link antigen recognitionwith T cell responses consistof the activation of enzymes,recruitment of adaptorproteins, and production ofactive transcription factors

• Immunologic synapse is theregion of contact between theAPC and T cell, including theredistributed membraneproteins

Functional responses ofT lymphocytesto antigen and co-stimulationSecretion of cytokines and expression ofcytokine receptors

IL-2 was originallycalled T cell growthfactor• The first cytokine to

be produced by CD4+T cells, within 1 to 2hours after activation,is interleukin-2 (IL-2)

Clonal expansion• T lymphocytes activated by

antigen and costimulationbegin to proliferate within 1 or2 days, resulting in expansionof antigen specific clones

• The expansion of CD4+ T cellsappears to be much less thanthat of CD8+ cells, probably100- fold to 1000-fold

• Effector cells of the CD4+helper lineage function toactivate phagocytes and Blymphocytes by expressingvarious surface molecules(CD40) and secretingcytokines

• CD40L is expressed onactivated helper T cells

Subsets of CD4 + helper T cells distinguishedby cytokine profiles• TH1

• TH2

• TH17

• Regulatory T cells one subset mayconvert into another under someconditions

Functions of CD4+ T CellSubsets

The TH1 Subset

• TH1 cells stimulatephagocyte-mediatedingestion and killing ofmicrobes, a key componentof cell-mediated immunity

• IFN-γ also stimulates• The expression of class II

MHC molecules and B7costimulators

• The antibodies production

Functions of CD4+ T CellSubsets

The TH2 subset

• TH2 cells stimulate phagocyte-independent, eosinophil-mediatedimmunity, which is especiallyeffective against helminthic parasites

• Cytokines produced by TH2 cells,such as IL-4, IL-10, and IL-13,inhibit the microbicidal activities ofmacrophages and thus suppress TH1cell– mediated immunity

Functions of CD4+ TCell Subsets

The TH17 Subset• TH17 cells induce

inflammation, whichfunctions to destroyextracellular bacteria andfungi and may contribute toseveral inflammatorydiseases

Development of TH1,TH2, and TH17 Subsets• The generation of these subsets is regulated

by the stimuli that naive CD4+ T cellsreceive when they encounter microbialantigens

• The most important transcription factors forthe three subsets are T-bet, GATA-3, andRORγT for TH1, TH2, and TH17, respectively.

• TH1 subset is driven by a combination of thecytokines IL-12 and IFN-γ

• TH2 cells is stimulated by the cytokine IL-4

• Development of memory T lymphocytes

• Decline of the immune response• Apoptosis

• Homeostasis

Thank you