T Cells/TCRs/APCs - Sant'Angelo 4/4/16 Flashcards
cells of innate immunity which also have adaptive immunity fx
professional phagocytes
- macrophages
- neutrophils (PMNs)
NK cells
dendritic cells : phagocytosis, antigen presentation, production of cytokines
- antigen presenting (mDC)
- interferen producing (pDC)
antigen presenting cells
initiators of adaptive immune response
collect proteins (many self, some pathogenic), break them down, present peptides to T cells
- enables T cells to respond, if necessary → adaptive immune response
what happens when a naive T cell comes across an MHC-peptide complex that requires a response?
naive T cell → differentiation into effectors T cell and memory T cells
-
effector T cells: produce effector molecules like cytokines (IL4, IFn gamma, etc)
- stick around for a while (like antibodies), contribute to “protective immunity”
-
memory T cells: long-lived, antigen-specific, able to generate rapid response on reexposure
- contribute to “immunological memory”
clonal selection hypothesis
lymphocytes mature in lymphoid organs (bone marrow or thymus) in the absence of antigens
clones of mature lymphocytes (each specific for single antigen - collectively specific for diverse selection of antigens) enter lymphoid tissues, where they’ll encounter antigens presented by APCs
- antigen specific clones are selected/activated by antigens → antigen specific immune response occurs!
T cell recognition of MHC-peptide complex
TCR recognizes both
- contact residue of peptide
- polymorphic residue of MHC
recall: MHC selectively binds peptides based on their anchor residues in “pockets”
costimulation of T cells
link to innate immune response
important role in….__________
T cells must receive 2 signals in order to be fully activated
- TCR binds to to antigen-HLA complex on the DC or APC → signal 1, primes T cell for activation and expansion once..
- CD28 binds to B7 molecules → costimulatory signal, signal 2
naive CD4/CD8 T cells require both to be activated
link to innate immunity
costimulatory molecules are upregulated on APCs in response to signals from the innate immune response
important role in TOLERANCE
“resting” APC is costimulator-deficient → no T cell response/anergy (fx unresponsiveness)
- prevents autoimmunity!
- in order to get the T cells going, you need the costimulator, which won’t be seen unless the APCs are activated by infection or innate immunity → TOLERANCE
once APCs are activated by microbes and innate immune response → increased expression of costimulators (B7-CD28 interaction), secretion of cytokines (IL12)
- leads to T cell survival, prolif, diff → effector and memory T cells!
consequences of inability to costimulate T cells
lack of costimulation → inhibition of T cell response
- cancer: malignant tumors express tumor restricted antigen (TRA) but no costimm molecules → T cells can’t be activated, even if specific for TRA (anergy) → tumor grows
- makes tumors hard to clear
how do you turn off a T cell response?
T cell responses must be turned on (costimulation by signal1 TCR-antigen/HLA binding and by signal2 innate/infection→B7/CD28 binding) and also turned off
crosslinking of CD28 and subsequent activation of T cells leads to upreg production of CTLA-4
- CTLA-4 binds to B7 (more avidly than CD28) → shuts down T cell response, prob by multiple mechs
if you have an uncontrolled immune response (toxic shock syndrome), get massive production of cytokines - cytokine storm - which can be fatal
therapeutic costimulatory blockade
if a person has overactive T cells → aberrantly causing autoimmunity
introduce soluble version of CTLA-4 that’s not bound to APC : CTLA-4 Ig
- does what regular CTLA-4 would do, interrupts the abberant activation by blocking costimulation via signal2
thought: doesnt this shut down ALL T cell response?
not as far as we can tell…
enhancing tumor immunity via blockade of CLTA-4 function
development of monoclonal antibody YERVOY that binds to CTLA-4, blocks its interaction with B7!
- keeps T cell activated, potentiates anti-tumor response
- typically though, also has some autoimmune effect :(
**note, B7 has 2 versions, B7.1=CD80, B72=CD86
big time application of YERVOY : life extension and/or cure of late stage melanoma patients for whom all other treatment options have failed
components of TCR complex: T cell activation
activation cascade
how do T cells stay associated with MHC long enough for all this to happen?
TCR is a heterodimer (alpha and beta chains) transmembrane protein BUT…its cytoplasmic regions do very little
→ there must be other players involved in the production/transduction of the signal that TCR binding generates into the cell
enter: complex of proteins collectively referred to as CD3 (2 pairs of epsilon and gamma chains; pair of zeta chains which interact directly with TCR)
* CD3 has ITAMs (immunoreceptor Tyr-based activation motif)
as part of early signaling events in T cell activation, antigen recognition occurs → TCR complex and coreceptors cluster on a lipid raft
- Lck (lympocyte-specific protein Tyr kinase) phosphorylates the Tyr residues in ITAMs
- ZAP-70 (zeta-chain associated protein) binds to P-Tyr and P’s adaptor proteins, such as LAT (linker for activation of T cells)
- cascade which will ultimately change gene expression
T cells have relatively low affinity for MHC, so make use of various ligand-receptor pairs to stabilize interactions
- LFA1 : ICAM1 [APCs, endothelium ligand]
- VLA1 : VCAM1 [endothelium]
- way into CNS! as in multiple sclerosis, destroying neurons
functional specialization among T cell subsets
essential for immune system fx
CD8 T cell : cytotoxic T cell, recognizes (mainly) viralpeptide-MHC I complex → kills infected cell
CD4 T cell : helper T cell
- Th1 - recognizes bacterialpeptide-MHC II complex → activates macrophage
- Th2 - recognizes antigenicpeptide-MHC II complex → activates B cell
main subsets of CD4+ T cells
- signature cytokines
- immune reactions
- defends host against…
- role in disease
Th1 → IFN-gamma
- macrophage activation; IgG production
- intracellular microbes
- autoimmune diseases, tissue damage associated with chronic infection
Th2 → IL4, IL5, IL13
- mast cell, eosiniphil activation; IgE production; “alternative” macrophage activation
- helminths
- allergic disease
Th17 → IL17A, IL17F, IL22
- neutrophilic, monocytic infl
- extracellular bacteria; fungi
- organ-specific autoimmunity
regulatory T cells
(Tregs)
key for tolerance
recognition of self antigen in tissues or lymph nodes → Tregsexpress specific tf FOXP3
- directly inhibit T cell activation and effector T cell fx
- produce inhibitory molecules (CTLA-4)
- affect DCs
- express high levels of CD25 (receptor for IL2 - critical for T cells proliferation) → Tregs sequester IL2, prevent it from spurring Treg proliferation
why do we need such a large number of TCRs?
(1015-1018)
peptides from pathogens are presented to T cells via MHC
- need high variety/diversity of TCRs to recognize the variety/diversity of pathogens
issue: if pathogen mutates in a way that its peptides can’t be presented to MHC → T cells can’t respond!
- ex. simian immunodeficiency virus (monkey analog of HIV) mutates rapidly to change the a.a.s that would anchor them to MHC (so as to avoid triggering immune resp!) → “CTL escape” hypothesis
