T Cell Immunity Flashcards
Kinetics of a T cell response
- clonal expansion
- Effector response
- Decline (homeostasis)
- memory
T cell homeostasis
-needs MHC and IL7 to survive
T cell life
- enter lymph nodes across high endothelial venules in cortex
- monitor antigen presented by macrophages and dendritic cells
- if don’t see antigen leave lymph node
- if see antigen-proliferate and differentiate to effector cells
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 nodes and of effector and memory t cells to sites of infection
- strengthen adhesion with APCs-integrins, affinity of ingetrins increased by cytokines produced during IF and Ag recognition
- signal transduction-CD4 and CD8 coreceptors recognize MHC, CD28, CD40L are receptors for costimulators expressed on APCs
LFA-1 and ICAM-1
- lymphocyte function associated antigen 1
- Intercellular Adhesion molecule 1
- T cells binds APC via LFA1 and ICAM1 interactions
- starts out low affinity, then TCR binds, then increase in affinity by conformational change
T cell activation
-needs 2 signals- TCR and costimulation
signal 1
- antigen recognition
- ensures that the response is antigen specific
-signal 2
- microbes or substances released during innate 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 co stim signal
- needs to be bacteria to activate-which can then show non bacterial protein
CD28
-needs to bind to B7 for co stimulation
CD28 ligands
B7-1 and B7-2
- in general induction of B7-2 expression follows faster kinetics and usually reaches higher expression levels than the induction of B7-1
- B7-2 is the major initial ligand for CD28, while B7-1 is expressed later and sustains T cell activation
B7-1
- CD80
- absent from unstimulated cells (macrophages)
B7-2
- CD86
- constitutively expressed at low levels on unstimulated DCs and blood monocytes
CD28 isn’t everything
- some T cell responses, from CD8 or deltagamma T cells are CD28 independent
- high avidity responses to certain viruses are CD28 independent
- in the presence of a strong signal 1, CD28 mediated co stimulation is not required
- other costimulatory pathways are possible
TH1 cells
- give macrophages 007 and induces B cells to produce opsonizing antibody
- TH1 cell makes IFN gamma, TNFa, CD40 ligand (to bind with CD40 on macrophage), Fas ligand, CM-CSF, IL3, TNFb, CCL2
- bacteria are in macrophage vesicles
- recognizes peptide/MHC class II
- activates infected macrophages
- cell mediated immunity
TH2 cells
- respond to B cells with antigens on their antibodies
- tell B cells to turn into plasma cells
- makes IL4,5, CD40 ligand (to bind with CD40 on B cell), GM-CSF, IL3, IL10, TGFb
- pathogens are in extracellular fluid
- peptide/MHC class II on B cell
- humoral immunity-uses TH1 cells as well
CTL
- cell mediated immunity
- pathogens in cytosol
- recognizes peptide/MHC class I
- kills cell
Stages of CD4 T cell activation
- naive CD4 T cell
- proliferating T cell
- immature effector T cell (TH0)
- differentiates into TH1 or TH2
TH1 and TH2
- both need additional help other than CD28
- CD40 is used to tell cells to do their jobs too
- induce a lot of cytokines-see slides
killer T cell
- makes Fas ligand to bind with Fas on infected cell
- makes perforin, granzymes, granulysin, IFN gamma, TNF a and b
IFN gamma and CD 40 ligand
-activates macrophage to destroy engulfed bacteria
Fas ligand for TNFb
-kills chronically infected cells, releasing bacteria to be destroyed by fresh macrophages
IL2
-induces T cell proliferation, increasing numbers of effector cells
IL# and GM-CSF
-induces macrophage differentiation in the bone marrow
TNF a and b
-activates endothelium to induce macrophage binding and exit from blood vessel at site of infection
CCL2
causes macrophages to accumulate at site of infection
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 (INF gamma, TNF, Fas L, IL2)
- primary CD8 cells may or may not require CD4 cell help
killing mechanisms
- granule exocytosis-predominant pathway (FAST killing)-granzymes and perforin
- expression of cell surface TNF family effector molecules (slow killing)-membrane TNF, lymphotoxin, Fas ligand, Trail
- secretion of soluble toxic cytokines (slow killing) TNF and interferon gamma
granule exocytosis
- activation induced re-orientation of granules to site of interaction in T cell
- release of perforin and granzymes
- granzyme B cleaves pro caspases
- induces apoptosis in target cell
- caspase-DNA fragmentation
- mito damage-cyto c release
released lytic granules
- dont kill CTL because surface cathespin B protects it
- proteinase inhibitor 9-serpin that inhibits granzyme B expressed by CTL, DCs, endo cells, some tumors
shut down of T cell response
- activated T cells express CTLA-4
- leads to functional inactivation
- some cells apoptose
- some cells stay for memory
CTLA-4
- binds B7 (on macrophage) instead of CD28 and has higher affinity than CD28
- delivers inhibitory signals to activated T cells
other factors for T cell shut down
- elimination of Ag
- elimination of other stimuli
- IL2/IL2R signaling (T regulatory cells grow by IL2 but inhibit it to stop other T cells growing too much)
- killing by immunoregulatory cells (Fas/FasL)
