Veeery nice lecture ))) SYNOPSIS *CD4+ T helper (T4) lymphocytes* 04:19 T4 lymphocytes produce different sets of cytokines to modulate function of other cell types 04:50 There are different effector T4 cell types: Th1, Th2, Treg, Tfh, as well as Th9, Th22 (and others..?) 07:25 What cytokines polarize naive T4 cells towards an effector Th cell? 08:11 Specific sets of polarizing cytokines activate a unique transcription factor ('master gene regulator') in naive T4 cells which leads to their differentiation into effector ones marked by the production of certain cytokines 09:47 The generation of effector T4 cells really depends on innate immune system molecular and cellular components: pattern recognition receptors (PRRs) and antigen presenting cells (APCs) (besides non-immune competent cells such as keratinocytes, eneterocytes...) *Th1 lymphocytes* 11:50 The main polarizing cytokine for Th1 cells is IL-12 (12:29) stimulating T-Bet transcription factor (TF) expression which governs Th1 cells to produce IFN-γ (12:39) acting as a para- and autocrine agent stimulating naive T4 and Th1 cells in a positive feedback loop manner respectively (13:08) 13:29 In turn, IFN-γ is involved in enhancement of APCs, cytotoxic CD8+ T lymphocytes (CTLs); protection against intracellular bacteria, viruses (13:43). 13:50 IFN-γ secreted by Th1 cells binds to its receptor on macrophages (Mф) and additionally activates them besides other factors collectively improving the efficacy of processing phagocytosed (internalized) an intracellular pathogen in their vesicles 15:05 One of those types of Th1 controlled intracellular pathogens is the members of _Mycobacterium_ genus (including _M. tuberculosis_). Th1 cells are important in granuloma formation -- structures in lungs observed by X-ray where the bacteria are surrounded by several layers of activated Mф (16:05) constantly phagocytosing the pathogen to keep the infection localized and not disseminated 17:16 So, IFN-γ is crucial in Th1 response in general as illustrated by the experiments in mice infected by _Mycobacteria_ spp. bacteria: (17:43) almost 100% of IFN-γ gene knock-out (KO) mice rapidly die after BCG infection by day 60 compared to the wild-type mice because the IFN-γ KO mice do not have efficient Th1 immune response. *Th2 lymphocytes* 18:24 IL-4 deviates naive T4 cells to Th2 fate (IL-33 is another possible polarizing cytokine 19:39) IL-4 leads to GATA-3 TF expression in naive T4 cells which stimulate IL-4, IL-5, IL-13 cytokine genes transcription. 19:15 The secreted IL-4 provides a positive feedback for Th2 and naive T4 cells. 19:47 Th2 protects against extracellular pathogens (multicellular pathogens, e.g. helminths). 20:24 The secreted IL-4 in mice stimulate IgG1 class-switch recombination (CSR), in humans - IgG4; IL-4 also stimulates IgE production which can lead to mast cell activation (besides a large repetitive extracellular antigen (20:44) followed by degranulation of a set of compounds (e.g. histamine) (20:29, 31:00). 20:32 IL-4 and IL-13 stimulate intestinal mucus secretion and peristalsis; IL-13 increasis enterocyte prolifiration and turnover (27:57). 20:36 IL-5 activates eosinophils and contribute to their recruitment to the site of infection (27:57). 21:30 Th1 and Th2: summary on polarizing cytokines, master gene regulators, effector cytokines, main targets. 22:22 The cytokines produced by subtypes of Th cells control immunoglobulin CSR (the table is for mice). 23:40 IL-12 (say from Th1) and IL-4 (say from Th2) are antagonists. IL-12 activates STAT4 which activates T-Bet which in turn inhibits GATA-3 and stimulate IFN-γ production but inhibits IL-4 and IL-5. So, IL-12 promotes Th1 cell development from naive T4 cells. IL-4 activates STAT6 which activates GATA-3 which in turn inhibits T-Bet and IFN-γ production but stimulates IL-4 and IL-5 synthesis. So, IL-4 promotes Th2 cell development from naive T4 cells. _Th1 sometimes are good but Th2 not_ _In leprosy_ 24:53 _M. leprae_ causes 2 polar clinical forms of leprosy: tuberculoid (low infectivity, microbes are present at low levels, localized infection, so rather mild) and lepromatous (high infectivity, many dividing microbes within Mф, disseminated infection, no response to _M. leprae_ antigens, so severe). In the tuberculoid leprosy patients Th1 immune response is dominant: IFN-γ, IL-2, LT-α are elevated (25:47), whereas in lepromatous leprosy patients Th2 prevails: IL-4, IL-5, IL-10 are increased (25:57). So, some patients develop Th1 immune response and the others -- Th2 immune response to the _M. leprae_ (26:05). _In leishmaniasis_ 26:27 BALB/c mice infected with _Leishmania major_ develop Th2 immune response (with specific IgG1), fail to cure infection, and die. If BALB/c mice are administered anti-IL-4-Ab, Th2 immune response is blocked and Th1 immune response (with specific IgG2a) is developed, the parasite is eliminated, and the animals survive. *Does C57BL/6 develop Th1 (with specific IgG2c) in **_L. major_** infection and survive?* _So, is Th2 immune response -- responsible for extracellular pathogens control -- able to deal with extracellular M. leprae_and L. major? No, Th1 cells are protective._ [PMID: 26066544] _In asthma_ 29:03 In asthma, Th1 response seems to be favorable, but Th2 is again harmful. T-Bet+/+ mice (with normal Th1 response) show normal alveolar and bronchiola microscopic picture. Contrary, T-Bet-/- mice (with impaired Th1 response) develop airway inflammation, collagen deposition and excessive mucus production obturating airways. _Th2 lymphocytes are good_ 27:57 Meanwhile, Th2 are protective in case of helminth infestations: their IL-13 contribute to enterocyte enterocyte prolifiration and turnover, as well as mucus secretion by goblet cells, and along with IL-4 the cytokines stimulate peristalsis and thus contribute to mechanicanical expell of the pests. IL-5 activates and recruits eosinophils which can carry specific IgE and degranulate anti-parasite substances. IL-9 and IL-13 recruit mast cells which can also carry specific IgE and their degranulation can cause muscle spasm and diarrhea that also contributes to mechanicanical expell of the pests. So, binding of the epitopes on parasite by IgE+FcεRI+ eosinophils and mast cells leads to their degranulation and release of inflammatory mediators (31:00) On the contrary, in the case of helminths Th1-driven immune response is ineffective and self-destructive It is characterised by irrelevant Mф activation and IFN-γ triggered production of ineffective IgG. 30:00 Several types of helminths -- representatives of Nematodes, Trematodes, Cestodes -- controlled by Th2 lymphocytes, cause different severe infestations. 31:00 Eosinophils and mast cells are indispensable in Th2-driven anti-helminth immune response. _Th2 lymphocytes sometimes are bad and ugly_ 32:25 Autoimmune disorders incidence prevails in developed countries, but incidence of helminth infestations dominates in developing countries. 33:13 Hygiene hypothesis: in developed countries encounters of the Th2-dependent antigens are rare, and this fact might serve as a background for Th1/Th2 disbalance observed in autoimmune disorders and allergies (eczema, rhinitis, asthma) where Th2 cells bias the immune response. 34:47 Hygiene hypothesis seems to be helpful in describing the distribution of the pathologies between city and rural area human populations, between families with less and more number of children, etc. 36:06 ? *Th17 lymphocytes* 38:00 Th17 cells' classic cytokines are IL-17A and IL-17F. 38:07 Polarizing cytokines for Th17 is a _combination_ of either (TGF-b + IL-6) or (TGF-b + IL-23), so TGF-b + a proinflammatory stimulant (41:43) 38:44 Naive T4 cell will start express RORyt TF which will lead to synthesis of effector cytokines IL-17A, IL-17F, IL-22. 38:56 IL-17 cytokines (say from Th17 cells) turn neutrophils on, both cell types are important in protection against fungi and extracellular bacteria 39:48 But Th17 cells unfortunately contribute to autoimmune diseases (multiple sclerosis) *Follicular helper T lymphocytes* 40:19 Tfh cells specifically act in B cell follicles to help B cells 40:32 T4 will differentiate to Tfh differon under IL-6 and IL-21 resulting in Bcl-6 TF expression followed by IL-4 and IL-21 effector ctokines production facilitating B cells in B cell follicles *Treg lymphocytes* 41:09 Tregs is another T4 cell subset. 41:33 Polarizing cytokine for Tregs is TGF-b. So, TGF-b alone is sufficient for Treg development (42:03). But another way to become a Treg exists (44:25). 42:10 Master gene regulator for Tregs is FoxP3, effector cytokines for Tregs are IL-10, TGF-b. 42:24 Tregs are indispensable in suppression of inflammation, immune response in general (including anti-tumor) by (42:29) suppressing T4, T8, B lymphocytes and others. Treg-driven suppression of autoreactive T4 cell clones requires them to interact with the same APC presenting autoantigen-relevant epitopes (Parham, Fig. 7.19) 43:46 Tregs act via several mechanisms: by cytokine deprivation (e.g. by trapping IL-2 with their IL-2R), by producing inhibitory cytokines (e.g. TGF-b), by APC inhibition, by being cytotoxic. -------------------------------------------------------------------------------------------------------------- (The comment contains unmarked citations from Prof. Brianne Barker's speech and from the excerpts cited in the presentation.)
