11. Lymphocyte Activation Flashcards
what is clonal selection vs clonal expansion/proliferation?
The adaptive immune response begins with the recognition of antigen by a naïve clone expressing a single specific cell surface antigen receptor (clonal selection).
This antigen recognition stimulates a series of signal transduction events, with the help of costimulatory molecules, that ultimately induce changes in cell size, cell cycle, and gene transcription (clonal expansion/proliferation).
3 requirements for T cell activation?
- antigen presentation by APCs
- adhesion molecs (eg T cell has LFA-1 and APC has ICAM-1)
- costimulation
what are the assocaited signaling chain molecules for TCR (since TCR can’t signal alone)?
CD3 and Zeta chains with ITAM
T cells require adhesive interactions to initiate and sustain contact with the APC. A class of molecs called _____ fulfills this funciton. What is one example of a super important T cell version?
integrins;
An important T cell integrin, LFA-I, mediates adhesion with APC via contact with its ligand ICAM. The affinity of LFA-1 for ICAM is increased after antigen activation. Loss of adhesive interactions greatly inhibits the ability of T cells to effectively mount immune responses, as manifested in the clinical disease lymphocyte adhesion deficiency (LAD).
In a weak adhesion between APC and Tcell, there is no T cell response. What signals act on T cell integrins to facilitate response and what is the outcome?
signals delivered by chemokines and antigen recognition act on integrins to create clustering and increase in affinity of integrins (this facilitates strong Tcell-APC ahesion and thus T cell response)
If T cells are activated in the absence of Signal 2 (costimulation), what happens?
T cells become unresponsive to antigen (even if costimulation is added) = no response or functional inactivation (“anergic”)
what APC molecule is commonly brought to the surface when the APC is activated to facilitate T cell activation?
B7 (binds to CD28 on T cells)
What molecule serves as an inhibitory costimulatory molecule?
CTLA4 (binds to B7 on APC) or PD-1 (binds to PD-1L on APC)
what happens to T cells re: proliferation after stimulation by MHC 1?
- T cell activation by antigen and costimulator
- secretion of IL-2 from T cell
- Expression of IL-2Ralpha (CD25) chain; formation of high affinity IL-2RaBg complex
- IL-2 induced T cell proliferation
expression/function of costimulatory molecules and T cell activation is modulated in space or time?
both (eg stimulation of CD8 T cell by DC with MHC class I and B7-CD28 activates the T cell....the T cell then brings CTLA4 to the cell surface from intracellular vesicle. Then CTLA4 AND CD28 bind to the DC along with MHC I and the negative signal wins to downregulate the survival and responses of the T cell
OR
eg T cell is activated by MHC and costimulation and thus is trafficked to peripheral tissues. But, in the peripheral tissues, there is inflammation and the T cell PD-1 binds to PDL on inflammed tissue and this downregulates the antigen-experienced T cell function…think of how cancers have evolved this to stop T cells and protect themselves!)
What are the 3 steps of the T cell activation process?
- intracellular signaling mechanisms
- formation of the immunological synapse
- production of IL-2
does TCR or associated chains (CDR3 or zeta) have kinase activity?
neither
The activation of T cells begins with the transduction of intracellular signals through the TCR/CD3 complex. The signaling begins with the activation of ____ family tyrosine kinases, eg ______.
src family tyrosine kinases, lck and fyn
The src family tyrosine kinases lck and fyn add phosphate to what?
tyrosine residues found int eh cytoplasmic tails of the CD3 complex in sequence motifs called immunoreceptor tyrosine-based activation motifs (ITAMs)
phosphorylation of ITAMS by src family kinases leads to recruitment and subsequent activaiton of ____ kinase. When activated, this kinase what happens?
ZAP-70. Activated ZAP-70 phosphorylates linker/adapter molecs like LAT and SLP-76, which couple to ras activation, calcium flux and activation of calcineurin phosphatase, and activation of PKC. These distal events lead to MAP kinase activation, cytoskel reorganization, and ultimately to mobilixzation of TFs in the nucleus (NFkB, NFAT, and AP-1)
what do cyclosporine A and FK506 (tacrolimus) do?
inhibit calcineurin (so failure to activate NFAT and so many critical genes are not induced by TCR-stimulation)
(polymorphisms in metabolizing enzymes like CYP450 can affect dosage and plasma levels of cyclosporine and FK506, altering toxicity and efficacy)
what are the three major TFs to induce new formation of IL-2 re: T cell activation?
NF-AT, AP-1, and NF-kB
integrin adhesion leads to the creation of one big TCR cluster in the cell. True or false?
false - leads to microclusters of TCRs
____ binds to phosphotyrosines of zeta chian and phosphorylates multiple substrates in T cell activation.
ZAP-70
what are 2 oncogenes in the Ras/MAP-kinase pathway in T cells?
lck and Ras
what TF does Ras get us to in T cells?
AP-1
