Lecture 6: TH 1 Cells (Type 1 Response) PDF

Lecture 6: TH 1 cells (Type 1 response) TH 1 Signal 3 (polarizing cytokines): IFN-gamma and IL-12 Transcription factors that get activated: STAT 1 and STAT 4 Master transcriptional regulator: T-bet gene Effector cytokine: IFN-gamma TH1 activates cellular immunity: - can activate Macrophages/increase...

Lecture 6: TH 1 cells (Type 1 response) TH 1 Signal 3 (polarizing cytokines): IFN-gamma and IL-12 Transcription factors that get activated: STAT 1 and STAT 4 Master transcriptional regulator: T-bet gene Effector cytokine: IFN-gamma TH1 activates cellular immunity: - can activate Macrophages/increase their effectivity -can Activate and differentiate naïve cytotoxic T lymphocytes precursors into effector CTL (through CD40L binding) Responds to Intracellular pathogens, ex. intracellular bacteria (eg M. tuberculosis & Salmonella), intracellular parasites (eg Leishmania & Toxoplasma) and viruses TH 1 functions Secrete IFNg at point of interaction and Target macrophages (TH 1 cell TCR recognizes pMHC-II on macrophage surface) to aid in the killing of microbes that persist in macrophage vesicles When talking about TH1 cell response, it is always known as the Type 1 response TH 1 cells activate macrophages → Some pathogens can persist in macrophages: they can either inhibit fusion of phagosome & lysosome or prevent acidification so lysosomal proteases can’t activate TH 1 cell can recognize pMHC class II on surface of the cell and use its CD40L to bind CD40, and secrete IFNgamma to boost antimicrobial activity & production of TNFa from the macrophage →this boost is called “classically activated macrophages” or activated M1 macrophages Function 1: Activate M1 macrophages = induced by TH 1 and have a boost to their antimicrobial mechanisms TNFa secreted leads to autocrine signaling which sends survival signal to macrophage CD40L binding activates macrophages and increases expression of IL-12 – which is part of signal 3 to differentiate into TH1 cells →this CD40L is also involved in Dendritic cells for cross-presentation but this is ONLY seen in dendritic cells not in macrophages TNFalpha & IFN-gamma together lead to intracellular signaling that increases expression of MHC I & II, CD40, B7, IL-12 which further activates TH 1 cells (feed-forward loop or positive feedback loop) **note that IFNgamma from effector CTLs can also activate M1 macrophages Function 2: Killing infected macrophages using FasL mediated killing Can happen in case of chronically infected macrophages TH 1 cells recognize pMHC-II on infected macrophage and also expresses FasL on TH 1 cell binds Fas on infected cells, triggering apoptosis →recall that FasL is also found in CTLs Bacteria is released from macrophage and can be phagocytosed by other macrophages Function 3: Help CD8+ T cells get activated TH 1 cell can secrete IL-2 and stimulate CD8+ T cell proliferation Would occur in the secondary lymphoid organ (lymph node) – vs macrophages that get activated at site of infection Function 4: Stimulate increased differentiation of monocytes in bone marrow TH 1 cells can secrete IL-3 and GM-CSF, which circulate in the blood and act on precursors in the bone marrow → an example of cytokines having an endocrine effect GM-CSF = Granulocyte-macrophage colony-stimulating factor (not tested) Function 5: recruiting more macrophages by adhesion molecules -Change expression of adhesion molecules, on neighboring endothelium to recruit more macrophages TH 1 cells secrete cytokines, TNFalpha and LTalpha, that induce these changes Function 6: Recruitment of macrophages by chemotaxis TH 1 cells secrete chemokine CCL2 that attract macrophages to site of infection M. Tuberculosis & TH 1-mediated responses M. tuberculosis infects macrophages in the lung and TH1 is very important because it is often resistant to anti-microbial effect of macrophages which can cause chronic infection →Granuloma formation can be created by a core of infected macrophages surrounded by layer of activated macrophages and TH 1 cells - the center often becomes necrotic, cells die from a combination of lack of oxygen and cytotoxic effect of activated macrophages →sometimes the other activated macrophages can destroy these granulomas but MOST of the time it cannot and drugs are needed (antibiotics) TH1 cells: - Signal 3: IFNg and IL-12 - Stat 1 and Stat 4 - Master transcriptional regulator: T-bet - Secrete IFNg, and other cytokines and chemokines Main TH 1 effector function is activating macrophages to kill intracellular pathogens - M1 macrophages are also known as “Classically” activated macrophages Other TH 1 effector functions - Killing infected macrophages - Providing help to activate CTLs - Inducing differentiation of monocytes in bone marrow - Recruiting macrophages to site of infection TH 2 cells (Type 2 response) Signal 3: IL- 4 Transcription Factors: Stat 6 Master transcriptional regulator: GATA-3 Effector cytokines: IL- 4, IL- 5, IL-13 Important role in response to helminths and parasites → Activates eosinophils, mast cells, and basophils if there is any dysregulation in TH 2 responses, this is what causes in allergies and autoimmune disorders Parasitic helminths: Multicellular worms that Colonize gut of animals and humans all over the world (1 billion people currently infected with a helminth!) they often cause chronic infection and not easy to treat TH 2 responses to helminths Can sometimes clear the pathogen, or not, in cases of chronic infection Reduce worm burden by a method called: “Weep and sweep” Facilitate tissue repair because these parasites damage tissue IgE antibodies are very important for immune responses against helminths M2 Macrophages are known as “alternatively activated macrophages” →M2 macrophages aid tissue repair and participate in worm killing and expulsion (ex. Increase smooth muscle contraction) - this is an alternative function TH 2 effector function 1: Promote cell turnover and mucous production IL-13 can increase mucus production by goblet cells & increase turnover of epithelial tissue, this turnover physically removes the helminth and promotes the expulsion of the parasite The mucous production is the “weep” in the “weep and sweep” response TH 2 effector functions 2: Enhance worm expulsion IL-13 can stimulate smooth muscle cells to contract which can lead to worm expulsion The “sweep” in the “weep and sweep” response TH 2 effector functions 3: Recruit and activate M2 Macrophages IL-4 and L-13 important for M2 macrophage activation → they can form granulomas to entrap worms and release toxic mediators directly onto the worm by antibody-dependent cell-mediated cytotoxicity (ADCC) ADCC: the killing of antibody-coated target cells by cells with Fc (antibody) receptors that recognize the region of the bound antibody TH 2 effector functions 4: Eosinophhil activation -IL-5 activates eosinophils and eosinophil granules contain major basic protein (MBP), which can kill parasites IgE antibodies bind antigens on parasite, eosinophils express receptors that recognize the Fc portion of IgE, so that eosinophils can then specifically target pathogen and degranulate to kills it TH 2 effector functions 5: Mast cell activation Cytokines activate mast cells. Mast cell granules contain histamine and other molecules which Increase vascular permeability, intestinal motility, and increase recruitment of inflammatory cells IgE antibodies coat parasite, mast cells express receptors that recognize the Fc portion of IgE (ADCC) Basophils can secrete IL-4 and IL-13, can activate goblet cells, allow vasodilation, binds to IgE (ADCC) and releases histamines Summary of TH 2 cells M1 macrophages: “Classically” activated macrophages Signal 3 (IL-4), effector cytokines (IL-4, IL-5, IL-13), master transcriptional regulator (GATA-3) Response to helminths (weep and sweep response) Activates granulocytes (eosinophils, basophils, mast cells) Tissue repair by M2 macrophages Impact on mucosa and smooth muscle to expel/control parasite M2 macrophages: “Alternatively” activated macrophages