T Cell Activation Flashcards
5 Components of T Cell Antigen Recognition
1-TCR binds antigen peptide
2- CD8 or CD4 binds MHC molecules (@ separate site than peptide binding cleft)
3- Adhesion molecules strengthen the binding (LFA-1 to ICAM of APC)
4- Co-stimulators on APCs bind receptors on naive T cell
5- Cytokines amp T cell response and guide differentiation
2 Co-Stimulators
- B7-1 or B7-2 on APC - CD28 of T cell (ESSENTIAL)
- ICOSL on APC- ICOS of T cell (activation of follicular helper T cells)
CD40
- on APCs
- Binds CD40L or CD154 on activated T cells
- Activate APCs to express more B7 co-stimulators and secrete more IL-12 (INDIRECT EFFECT)
What makes CD8+ activation more complicated than CD4+?
- Often requires antigen from cytoplasm of 1 cell to be cross presented by dendritic cell
- May require concomitant activation of CD4+ helper T cell (these helper T cells may release cytokines or membrane molecules that help activate CD8+ cells)
CD3 and Zeta Protein Signal Transduction
-Tyrosine kinases activated (ex- Lck and Fyn) —> phosphorylate tyrosine residues on CD3 and zeta proteins —> phosphorylated CD3 and zeta now recruit/activate ZAP-70 (zeta associated protein of 70 kD) —> ZAP-70 phosphorylates other target proteins including adaptor proteins/other enzymes
3 Transcription Factors Activated by T Cell Antigen Binding
- NFAT - transcription factor for many genes including IL-2 (for T cell proliferation)
- CALCIUM DEP
- AP-1 - enhances transcription of several T cell genes
- Nuclear Factor kB (NF-kB)
NFAT Activation
- CALCIUM DEP (need PLC-gamma to cleave PIP2 –> IP3 —> Ca++)
- Ca-calmodulin —> activates calcineurin —> removesP from cytoplasmic NFAT (NFATc) so it can move to nucleus for transcription
- **Immunosupressive drugs can inhibit calcineurin (ex - cyclosporin A and FK506)
AP-1 Activation
- ZAP-70 phosphorylation —> accumulation of adaptors —> recruitment of Ras or Rac and their activation by binding GTP —> cascade that activates specific MAP kinases (ERK and JNK are the final MAP kinases in path) —> induce expression of c-foc and phosphorylate c-Jun
- c-foc and phosphorylated c-JUN combine to form the AP-1 transcription factor
NF-kB Activation
- DAG activate PKC-theta —> PKC-theta initiates cascade that eventually phosphorylates IkB which targets it for destruction
- IkB normally binds NF-kB keeping it in inactive form so destroying IkB allows NF-kB to go to nucleus for transcription
What are the 4 main things responsible for T cell proliferation and survival?
IL-2 and CD28 receptors (when these dec once antigen destroyed … apoptosis of T cells)
phosphatidylinositol3 (PI3) kinase phosphorylates PIP2 —> PIP3 which activates AkT (also known as protein kinase B) —> stimulates expression of anti-apoptotic proteins
mTOR
How does a T cell’s metabolism change once activated?
- More glucose uptake
- Switch to anaerobic glycolysis (less ATP but prod of lipid and AA by-products needed as building blocks)
2 Types of T Memory Cells
- Central memory T cells - in lymphoid organs for rapid clonal expansion in future
- Effector memory T cells - in mucosa and peripheral tissues for rapid effector functions when antigen bound again
3 Steps of T Cell Response to Activation
- Autocrine cytokine action; T cells (mainly CD4+) produce IL-2 (w/in 1 or 2 hrs of activation) and also produce final chain of IL-2 receptor (alpha chain or CD25) so they can bind the very IL-2 they make (**survival and proliferation)
- Proliferation w/in 1 or 2 days (Higher in CD8+ than CD4+)
- Differentiation - into effector or memory
- Effector cells - gene expression specific to their role
- CD8+ - means to kill microbes
- CD4+ means to stimulate B cells and phagocytes; most important is CD40 L on membrane that binds CD40L on APCs to enhance binding —> cytokine prod
- Memory cells survive after antigen gone; once they bind antigen again in future they gain effector functions
- Effector cells - gene expression specific to their role
How do naive T cells enter lymph node?
- 1- naive T cells in blood engage in L-selectin mediated rolling in HEV; allows chemokines to bind CCR7 on T cells
- 2- CCR7 —> intracellular signals that activate/inc affinity of LFA-1 on T cells
- 3- Adhesion b/n LFA-1 and ICAM-1 on HEV
- 4- T cells exit blood vessel through endothelial junctions; now in T zone of lymph node
SiP and Migration
- sphingosine 1 phosphate) conc higher in blood/lymph than lymph node itself
- When T cell enters node the expression of SiP receptors increases
- If no antigen … T cell leaves via efferent lymph vessel; follow SiP gradient
- If T cell encounters antigen/is activated… SiP receptor expression decreases so T cell remains in node for several days allowing for proliferation and differentiation; then effector T cells re-express SiP receptors —> leads them out into circulation
- **FTY720 is SiP1 antagonist/inhibitor used for MS (prevents activated T cells from leaving lymph nodes to migrate to areas where they cause immune pathology)
