How do CTLs differentiate before becoming effectors?
Naive T cell stimulated by binding to MHCI and B7, and need stimulus of IL-2 (might make it autocrine or receive it from Th cell). Once activated Tc cells only need TCR and peptide.
Methods of CTL killing
Perforin + granzymes (cause apoptosis); lymphotoxin; Fas ligand. Always very specific.
aka TNF-a. Cytokine from CTL which induces apoptosis in cell which has lymphotoxin receptor
Fas ligand killing
cell surface protein which binds to Fas receptor on most cells. The interaction induces apoptosis. CTL cells also produce Fas receptor after some time so they kill each other off and avoid getting out of control
NK cell recognition
Activated by interferon, interleukin-2 and 12. KIR (killer inhibitory receptors) block NK cells from attacking normal good cell. Two recognition mechanisms: Recognize self protein on tumor or infected cell, or kill cells w/o adequate number of MHCI
NK cell killing
Perforin + granzymes (cause apoptosis); or ADCC: NK cells bind to AB bound to cell, secrete lytic enzymes, TNF, perforin
Compare NK and CTL
Cytokine acts on several cell types or produces several effects on the same cell
Several Cytokines acts on same cell
Cytokines act together to produce the effect
Cytokines counteract each other
TH2 cytokines and general effect
TH2’s produce IL-3, IL-4, IL-5, IL-10 and IL-13 when activated. These cytokines are stimulatory factors for B cell proliferation, antibody secretion and antibody class and isotype switching. Help a bit with AB, Macrophage activation, Delayed-type hypersensitivity, TC cell activation
TH1 cytokines and general effect
Th1 cells secrete IL-2, IL-3, GM-CSF, IFNγ and lymphotoxin, which normally induce inflammatory responses but can also help B cells under certain circumstances. Help for total antibody production, Help for IgE production, Eosinophil and mast-cell production
TH17 cytokines and general effect
IL-17 and IL-23, recruit and activate neutrophils. Protection from Infection (via IL-17?) from extracellular bacteria (Klebsiella, Bacteroides, Strept, Pneumoniae, Borrellia), fungi, yeast [Crypto, Candida]). Induction of autoimmune/inflammatory diseases like psoriasis (via IL-23?).
TH1 vs TH2 balance
Usually a teeter-totter b/w the two. rarely both.
Caused by super antigen from things like S aureus. Binds non specifically to MHCII and TCR, activating huge number of T cells, short-circuits immune system. Bad. NOT the same as endotoxic shock.
IL-2: A T cell growth factor, made by Th1 cells, also enhances activity of CTLs and NK cells.
IL-4: The key Th2 cytokine; made by Th2 cells, co-stimulates activation of antigen-primed B cells, stimulates proliferation and differentiation of B cells, as well as class switching to IgG1 and IgE.
IL-5: Made by Th2 cells, promotes growth and differentiation of eosinophils (=eosinophil growth factor); stimulates proliferation and differentiation of B cells, class switching to IgA.
IFN-gamma: One of the key Th1 cytokines, made by Th1 cells, CTLs and NK cells: increases expression of MHC, blocks IL4 induced class switch to IgE, inhibits proliferation of Th2 cells, promotes formation of ‘super-killing macrophages’ in DTH.
IL-10: Key Th2 cytokine which inhibits Th1 responses, made by Th2 cells and macrophages.
IL-12: Key promoter of Th1 responses, made by macrophages, acts with IL-2 to induce differen- tiation into CTLs, stimulates proliferation of NK cells, inhibits formation of Th2 cells. Consists of p35 and p40 subunits (the same p40 subunit is also found in IL-23 [p19 and p40]).
IL-1, TNFa, IL-6
IL-1, TNFα, IL-6: Mediators of natural immunity' made by macrophages when they are exposed to endotoxin or when they eat whole bacteria; directly responsible for the symptoms of endotoxic shock.
TNFα: Made by macrophages; delivered from the surface of TDTH cells which along with IFN-γ induce DTH (=activation of macrophages into a super-killing state, so they can kill microbes residing in the intravesicular compartment).
IL-3, GM-CSF: Induce production of granulocytes and macrophages in bone marrow.
TGFβ: Made by several cell types, helps to limit inflammatory response, promotes wound healing, induces class switch to IgA.
Cytokine receptor properties
Made of 2-3 polypeptides, binding site made of more than one. Genetic deficiency in cytokine receptor genes result in lots of immunodeficiency (cytokines can’t bind and act)
Delayed-type hypersensitivity (type 4). Basically Macrophage tries to kill pathogen but sometimes gets infected. TH1 cell (mediated by IL-12, IFN-gamma, TNFa) helps super-activates it to kill what it ingested. If it cannot do it, it undergoes apoptosis and other super-activated macrophages can clean it up. If it’s bad it forms a granuloma: wall of T cells around infected macrophages. (DTH is similar to TB test when a button forms)