T Cell-Mediated Immunity Flashcards
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
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
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
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
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
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
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
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
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
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
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)
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
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
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
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
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
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
Importance of lineage
-when a cell chooses a lineage they promote their own and suppress others by the cytokines that they produce
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
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
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
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)
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
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
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)
