Activation of macrophages, B cells, and other cells.
What is the function of effector CD8+ T cells (CTLs)?
Killing of infected "target cells" and macrophage activation.
What are "three signals" of T cell activation?
1) MHC recognized by cell 2) Co-stimulatory molecule for activation 3) Cytokines, particularly IL-2 (T cell growth factor for clonal expansion); there are also different cytokines necessary to cause T cell differentiation into subsets
What markers are on naive T cells?
L-selectin, LFA-1 (beta2-integrin), CCR7
What markers are on endothelial cells for naive T cell interaction?
L-selectin ligand, ICAM-1, CCL19 or CCL21
What is the function of the receptor:ligand pair between naive T cells and endothelial call molecules?
-L-selectin and L-selectin ligand: adhesion of naive T cells to high endothelial venule (HEV) in lymph node -LFA-1 and ICAM-1: stable arrest on HEV -CCR7 and CCL19/CCL21: activation of integrins and chemotaxis
What markers are on activated (effector and memory) T cells?
E- and P- selectin ligand LFA-1 (beta2-integrin) or VLA-4 (beta1-integrin) CXCR3, others
What markers are on endothelial cells for activated (effector and memory) T cell interaction?
E- or P- selectin ICAM-1 or VCAM-1 CXCL10, others
What is the function of the receptor:ligand pair between activated T cells and endothelial call molecules?
-E- and P-selectin ligand and E- or P-selectin: initial weak adhesion of effector and memory T cells to cytokine activated endothelium at peripheral site of infection -LFA-1/VLA-4 and ICAM-1/VCAM-1: stable arrest on cytokine activated endothelium at peripheral site of infection -CXCR3/others and CXCL10/others: activation of integrins and chemotaxis
What stimulates native T cells to become Treg?
What do Treg cells produce?
IL-10 and TGF-beta
What is the function of Treg cells?
What stimulates naive T cells to TH2 cells?
IL-4 AND IL-4, IFN-gamma from another source
What is produced by TH2 cells?
IL-4, IL-5, IL-10, and IL-13
What are the functions of TH2 cells?
Antibody production and defense against helminths
Antibody isotype switching, B cell proliferation, CD40L-CD40 signaling; decrease B7 and proinflammatory cytokines (macs and DCs); increase mast cell proliferation; increase eosinophil proliferation; decrease proinflammatory cytokines by macrophages, decrease ADCC, and decrease No production; increase APC MHC Class II and Th stimulation
What stimulates naive T cells to TH17 cells?
TGF-beta and IL-6 AND, IL-23, IL-27 from another source
What do TH17 cells produce?
IL-17 and IL-6
(TNF-alpha, IL-1, IL-8, GM-CSF, chemokines)
What are the functions of TH17 cells?
Neutrophil activation, inflammation, and defense against extracellular bacteria
What stimulates naive T cells to TH1 cells?
IL-12 AND, IL-4, IFN-gamma, and IL-27 from another source
What are the functions of TH1 cells?
Macrophage activation, inflammation, and defense against intracellular bacteria and protozoa
Increase DC licensing; increase B and T proliferation; increase B isotype switching; increase NK and Mac FcR and ADCC; increase Mac hyperactivation, cytokine secretion, NO production; increase Mac antigen presentation; increase Mac ROI production; increase Tc activation
What are the transcription factors to go from naive T cells to TH1 cells?
-STAT1 -STAT1, STAT4, T-bet, SMAD7
What do TH1 cells produce?
IFN-gamma, IL-2, TNF, GM-CSF
What are the transcription factors to go from naive T cells to TH2 cells?
-STAT2 -STAT3, STAT6, GATA3, c-Maf
What are the transcription factors to go from naive T cells to TH17 cells?
-STAT3? -STAT3, SOCS3, RORyt
What are the transcription factors to go from naive T cells to Treg cells?
Role of IL-12 and IFN-gamma in TH1 differentiation
Some T cells express CD40L upon activation and the APC may express CD40. This causes up-regulation of B7 as well as IL-12. Also, IFN-gamma being produced by NK cells also increases IL-12. TLRs could be responsible for induction of IL-12 (but not all TLRs). Between IFN-gamma and IL-12, stimulate differentiation into TH1 cell. TH1 cell produces more IFN-gamma.
TH2 cell differentiation requires?
IL-4 is recognized by IL-4R that leads to induction of STAT6 which then induces Gata3. There is IL-2 recognition that leads to STAT5. Gata3 + STAT5 turns on loci producing cytokines (IL-4) to get additional IL-4 production and final differentiation.
What products from TH1 cells cause B and T cell proliferation?
What products from TH1 cells cause B isotype switching?
What products from TH1 cells cause NK and Mac increased FcR and ADCC?
What products from TH1 cells increase Mac hyperactivation, cytokine secretion and NO production?
What products from TH1 cells cause increased Mac Ag presentation?
What products from TH1 cells cause increased Mac ROI production?
What products from TH1 cells causes increased Tc activation?
What products from TH2 cells causes decreased Mac and DC B7 and proinflammatory cytokines?
What products from TH2 cells causes decreased Mac pro-inflammatory cytokines, ADCC, and NO production?
What products from TH2 cells causes increased B proliferation, isotype switching, and CD40L-CD40 signaling?
IL-4, IL-5, and IL-13
What products from TH2 cells causes increased eosinophil proliferation?
What products from TH2 cells causes increased mast cell proliferation?
IL-3, IL-4, and IL-10
What cytokine is assisting TH1 proliferation?
What cytokine from TH1 cells causes negative effect on TH2 cells?
What cytokine from TH1 cells causes positive effect on TH2 cells?
What cytokine from TH1 cells causes positive effect on macrophages?
What cytokine from macrophages causes positive effect on TH1 cells?
What cytokines from TH2 cells exert negative effect on TH1 cells?
IL-4, IL-13, IL-10
What cytokines from TH2 cells exert negative effect on macrophages?
IL-4, IL-13, IL-10
Which produce IFN-gamma, TH1 or TH17?
Which produce IL-17A, TH1 or TH17?
Which produce IL-17F, TH1 or TH17?
Which express IL-12Rb2, TH1 or TH17?
Which express IL-23R, TH1 or TH17?
What do CTLs provide immune protection against? (4)
CTLs are activated in the context of what MHC molecule?
MHC Class I
What cytokine from CD4+ T (TH1) cells enables differnetiation of naive Tc to pre-CTL?
What cytokines cause differentiation from pre-CTL to armed CTL?
IL-12, IFN-gamma, IL-6
What are the 3 ways to get differentiated CTLs?
1) CD8+ T cells recognize antigen + costimulators on professional APCs and thus differentiate without helper T cells 2) CD4+ helper T cells produce cytokines that stimulate CTL differentiation 3) CD4+ helper T cells enhance the ability of APCs to stimulate CTL differentiation through CD40L:CD40 interaction
What is the mechanisms of killing infected cells by CTLs?
-Antigen recognition and conjugate formation (MHC Class I) (polarization of cytoplasmic granules) -CTL activation -Granule exocytosis -Detachment of CTL -Target cell death
What do CTLs use to adhere to target cells/infected cells?
LFA-1 (CTL) and ICAM-1 (target cell) interaction
What do the CTL granules contain?
Perforin and granzymes
What do granzymes do to the target cell?
Enter target cell through hole made by perforin and activate caspases within the target cell to cause apoptosis.
What is the "back up" system for CTLs if granules don't work?
When CTLs are activated, they also upregulate FasL (ligand) on their cell surface. The target cell expresses Fas. Interaction of these with the TCR will cause the FasL to induce other caspases to lead to target cell death.
What are other mechanisms CTLs use to cause cell death besides granules and FasL?
CTls produce cytokines (TNF, LT). If these bind to TNFR, get NF-kB production in target cell or cell death.
What two caspases are required for target cell lysis?
Caspase 8 and 9
Are Treg cells thymus derived or non-thymus derived?
Can be both.
What happens if a DC doesn't upregulate any costimulatory molecules when presenting to a T cell?
Get toleragenic DC and thus anergic T cell (non-responsive). Overall, get tolerance.
What is required for expansion of other Treg cells?
What do thymus-derived Treg cells suppressing (producing TGF-B) when activated?
TH2 cells as well as TH17 cells possible
What cytokine from Treg cells can exert functions on DCs?
TGF-B and IL-10
What enhances suppression of other T cell populations from Treg?
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