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Flashcards in T Cell-Mediated Immunity Deck (25)
1

T cell homeostasis

-Naive T cell has TCR binding lightly to MHC with self peptide in it
-also Naive T cell has IL-7R the IL-7 are just around
-the T cell survives

2

T cell homeostasis

-Naive T cell has TCR binding lightly to MHC with self peptide in it
-also Naive T cell has IL-7R the IL-7 are just around
-the T cell survives

3

Naive T cells in search of specific antigen

-T cells enter lymph node across high endothelial venules in the cortex
-T cells monitor antigen presented by macrophages and dendritic cells
-T cells that do not encounter specific antigen leave lymph node through lymphatics
-T cells that encounter specific antigen proliferate and differentiate and differentiate to effector cells

4

Functions of T cell accessory molecules

-Control routes of T cell migration: Selectins, integrins and chemokine receptors control migration of naive T cells in and out of lymph nodes and of effector and memory T cells to sites of infection

-Strengthen adhesion with APCs: integrins, affinitiy of integrins is increased by cytokines produced during inflammation and Ag recognition

-Signal transduction: CD4 and CD8 coreceptors recognize MHC molecules
-CD28/CD40L are receptors for costimulators expressed on APCs

5

Two signal model of T cell activation

1- TCR-MHC with the CD4 or CD8 helping: antigen recognition
2- Costimulation- microbes or substances released during innate immune response to microbes- ensures that the immune system responds to microbes and not to harmless antigenic substances; activated APCs express molecules which in turn bind to their respective ligands on T cells to deliver a costimulatory signal

6

The role of CD28 in T cell activation

-If there is proliferation and IL2 production, but if there is no second signal there is no response and the cell is anergic

7

Naive T cells in search of specific antigen

-T cells enter lymph node across high endothelial venules in the cortex
-T cells monitor antigen presented by macrophages and dendritic cells
-T cells that do not encounter specific antigen leave lymph node through lymphatics
-T cells that encounter specific antigen proliferate and differentiate and differentiate to effector cells

8

Functions of T cell accessory molecules

-Control routes of T cell migration: Selectins, integrins and chemokine receptors control migration of naive T cells in and out of lymph nodes and of effector and memory T cells to sites of infection

-Strengthen adhesion with APCs: integrins, affinitiy of integrins is increased by cytokines produced during inflammation and Ag recognition

-Signal transduction: CD4 and CD8 coreceptors recognize MHC molecules
-CD28/CD40L are receptors for costimulators expressed on APCs

9

Cell-cell interactions between T cells and APCs

-LFA1= Lymphocyte Function Associated Antigen 1
-ICAM1= Inter-Cellular Adhesion Molecule 1

-T cell initially bind APC through low affinity LFA1: ICAM1 interactions
-Subsequent binding of T cell receptors signals LFA1
-Conformational change in LFA1 increases affinity and prolongs cell-cell contact

10

Two signal model of T cell activation

1- TCR-MHC with the CD4 or CD8 helping: antigen recognition
2- Costimulation- microbes or substances released during innate immune response to microbes- ensures that the immune system responds to microbes and not to harmless antigenic substances; activated APCs express molecules which in turn bind to their respective ligands on T cells to deliver a costimulatory signal

11

The stages of CD4 T cell activation

-Naive CD4 cell (uncommitted)
-Proliferating T cell
-Immature effector T cell (Th0)
-TH1 cell- activates macrophages (liscence to kill; induces B cells to produce opsonizing antibody, (effectors: IFN gamma, GM-CSF, TNFalpha, CD40L, FasL)
-TH2 cell- activates cells to make neutralizing antibody; has various effects on macrophages, (effectors: IL-4,5,25, CD40L)

12

Activated TH1 cell

-IFNgamma and CD40L- activates macrophage to destroy engulfed bacteria
-FasL or TNF-B- kills chronically infected cells, releasing bacteria to be destroyed by fresh macrophages
-IL-2- induces T cell proliferation, increasing numbers of effector cells
-IL3+GM-CSF- induces macrophage differentiation in the bone marrow
-TNFalpha and TNFbeta- activates endothelium to induce macrophage binding and exit from blood vessel at site of infection

13

CD28 is not everything

-some T cell responses, such as those from CD8+ T cells are CD28 independent
-high avidity responses to certain viruses are CD28 independent
-in the presence of a strong signal 1, CD-28 mediated costimulation is not required
-CD28- mediated costimulation is not required for effector and memory T cells
-these responses may involve alternative costimulatory pathways

14

Three types of effector T cells

--CD8 T cells peptides and MHC I- cytotoxic killer T cells, communicates with virus infected cells and makes it apoptosis
-CD4 T cells: peptides and MHCII, TH1 cells- activates the macrophages to destroy the pathogens that are phagocytosized
-CD4 T cells, TH2 cells- activates an antigen-specific B cells and turn it to plasma cell

15

Roles of T cells in the immune response

-Cell-mediated immunity:
-typical pathogens: Vaccina virus, influenza, rabies, listeria; cytosol; cytotoxic CD8 T cells; peptide:MHC I complex on infected cell; killing of infected cell

-typical pathogens: mycobacterium tuberculosis, mycobacterium leprae, Leishmania donovani, Pneumoncystis carinii; Macrophage vesicles; TH1 cell; Peptide: MHC II complex on infected macrophage; activation of infected macrophages

Humoral immunity:
-Clostridium tetani, Staphylococcus aureus, Streptococcus pneumoniae, Polio virus, Pneumocystis carinii, Trichinella spiralis; extracellular fluid; TH1 and TH2; peptide: MHC II on antigen specific B cell; activation of specific B cell to make antibody

16

Killing mechanisms

-Granules exocytosis- predominant pathway (FAST KILLING)- granzymes and perforin
-express of cell surface TNF-family effector molecules(SLOW KILLING)- membrane TNF, lymphotoxin, FasL, Trail
-Secretion of soluble toxic cytokines (SLOW KILLING)- TNF and Inferferon gamma

17

Activated TH1 cell

-IFNgamma and CD40L- activates macrophage to destroy engulfed bacteria
-FasL or TNF-B- kills chronically infected cells, releasing bacteria to be destroyed by fresh macrophages
-IL-2- induces T cell proliferation, increasing numbers of effector cells
-IL3+GM-CSF- induces macrophage differentiation in the bone marrow
-TNFalpha and TNFbeta- activates endothelium to induce macrophage binding and exit from blood vessel at site of infection

18

Importance of lineage

-when a cell chooses a lineage they promote their own and suppress others by the cytokines that they produce

19

Cytotoxic (killer) T cells

-CD8 Tells:peptide and MHCI
-cytotoxins
-on the CTL there is FasL, the virus infected cells display Fas
-cytotoxic effectors- perforin, granzymes, granulysin, FasL, IFNgamma TNFB and A- proinflammatory

20

Priming a CTL

-CTL precursors- low frequency, no lytic granules, non-dividing
-Naive T cell and APC- interactions
-Results in:
-proliferation
-synthesis of granzymes and perforin
-cytokine production (INFgamma, TNF, FasL, some IL2)
-primary CD8+ T cells may or may not require CD4+ T cell help

21

Killing mechanisms

-Granules exocytosis- predominant pathway (FAST KILLING)- granzymes and perforin
-express of cell surface TNF-family effector molecules(SLOW KILLING)- membrane TNF, lymphotoxin, FasL, Trail
-Secretion of soluble toxic cytokines (SLOW KILLING)- TNF and Inferferon gamma

22

Granule Exocytosis Model

-activation induced re-orientation of granules to site of interaction
-release of perforin and granzymes- perforin creates holes in membranes, Granzymes B (aspase) cleaves pro-caspases
-induces apoptosis in targe cells- caspase activation- DNA fragmentation, mitochondrial damage (cytochrome C release)

23

Why don't released lytic granules kill the CTL?

-surface cathepsin B protects CTL from self-destruction after degranulation
-proteinase-inhibitor 9-serpin that inhibits granzyme B-expressed by CTL, dendritic cells, endothelial cells, some tumors

24

CTLA4

-cross linking of CD28 delivers the co-stimulatory signal during activation of naive T cells and induces the expression of CTLA-4 (CD12)
-CTLA-4 binds B7(CD80 or CD86) more avidly than does CD28 and delivers inhibitory signals to activated T cells

25

Regulation of T cell activation

-CTLA-4- master regulator
-Elimination of Ag
-elimination of other stimuli
-IL-2/IL-2R signaling (via T regulatory cells)
-killing by immunoregulatory cells (Fas-FasL)