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I. Th3/Treg
II. Mucosal Immunity/ Oral Tolerance
III. Th17


REGULATORY T CELLS
--CD4+ CD25+
--secrete high levels of TGFβ and IL-10
--multiple subsets:
***Th3—mucosal immune system, responds to food and microflora, absent in autoimmunity
***Tr1—can develop in the presence of IFNg, may shut down immune response when antigen is gone
***Treg—sometimes considered the bigger category containing Th3 and Tr1, sometimes grouped by themselves. When in their own category, it’s because they come out of the thymus already with CD25 on their surface. May be more contact dependent than Th3 or Tr1 (i.e. mediate function by touching cells rather than by secreting cytokines)

TGFβ and the Th3 RESPONSE
--Transforming Growth Factor β
--from Treg cells, same as IL-10
--tumors secrete TGFβ to shut down immune response
--B cells →IgA class switch
--B cells → inhibits growth
--inhibits growth of Macrophages
--IL-10 stimulates production of Th3
--immunosuppressive amounts of IL-10???

MUCOSAL IMMUNITY / ORAL TOLERANCE
--=a state of systemic unresponsiveness induced by antigen feeding
--want to not react to food or commensal bacteria
--natural immunologic event driven by exogenous antigen
--default response to harmless antigens in gut = immunological hypo-responsiveness
--dendritic cells appear to be the "gatekeepers" of oral tolerance
--intestinal mucosa has high basal levels of IL-4, IL-10, and TGFβ
--Th2 and Th3 cells preferentially generated in the GALT
--DCs from peyer's patch preferentially stimulate Th0 to produce high levels of IL-4
--DCs from spleen stimulate Th0 cells to make high levels of IFNγ

HOW FOOD TOLERANCE WORKS
You eat a food, let's say a protein-->protein denatured stomach acid-->absorbed whole and partially degraded by gut -->a few possibilities:
--2. Food antigen absorbed by gut epithelium, presented in MHC-I, HEALTHY TOLERANCE, no CD86 so no T cell activation, no TLR's, no cytokines
--1. Food antigen endocytosed by M cells-->M cell release the food antigen in the Peyer's Patch-->DC (gatekeeper) eats it-->DC makes IL-10 (-->Th3) and present the antigen to resident T cells-->two outcomes depending on presence of CD86 or other costim
--1a. if no costimulation then passive tolerance (anergy of T cells specific for food)
--1b. if costim (from any infx) then T cell is activated-->Th3-->active tolerance, T cells make TGFbeta (-->less B cells, less macrophages, IgA): low or high dose changes outcome
--1b. TWO POSSIBLE OUTCOMES if costim then active tolerance via Th3 cells making TGFbeta
----1b1. LOW DOSE induces of Th2 (IL-4/IL-10) and Th3 (TGFβ) secreting regulatory cells (IL-10 stimulates production of Th3) (could be due to microenvironment-- higher levels of IL-15, lower levels of TLRs) (Th3 CD4 T cells make TGFβ which triggers B cells specific for this antigen to produce IgA)
----1b2. HIGH DOSE (feeding) causes deletion or anergy of Th1 and Th2 cells, sometimes makes Th3 cells
--both CD4 and CD8 T cells make TGFβ in the gut
--food antigen is phagocytosed by a DC and carried to a mesenteric Lymph Node (MLN)-->DC presents antigen to CD4 and CD8 T cells-->T cells make TGFβ
--experiments with feeding to correct autoimmunity: give collagen to rheumatoid arthritis pts, small improvement, narrow therapeutic window

EFFECTS OF TGFβ
--downregulates Th1
--enhances differentiation of other Th3 cells
--downregulates production of IL-12 by DCs and macrophages

FOOD TOLERANCE FROM MY NOTES
--the GI tract has 400 square meters of surface area and over 500 species of bacteria
--less TLR's on macrophages and DC's in gut
--some enteric microbes no longer bind TLR's (bifidus)
--food in lumen crosses mucosa to peyers patches, mesenteric lymph nodes
--peyers patches and mesenteric lymph nodes constitute 80% of a person's immune system
--always active
--eating oil with food causes it to be absorbed lower in the tract, increasing the odds of allergy because there are more allergens down there
--eating fiber decreases allergies, pushes things through before they can trigger inflam
--M cells are between peyers patch and lumen
--M cells transport food via endosome to PP
--epithelial cells also take in food, have MHC-I
TWO TYPES OF TOLERANCE IN THE GUT: LOW AND HIGH DOSE
--low dose = foods rarely consumed --> CD4 response, TGFbeta shuts down response, no macrophages or CD8's involved
--high dose = eat it daily = body kills T & B cells specific for that food
--feeding --> develop a tolerance because increase Th3 response
--not working well yet experimentally
--collagen fed to rheumatoid arthritis pts--small improvement, narrow therapeutic window
--Th1-->TNFalpha-->leaky gut, crohns, colitis, increased intestinal permeability
--colitis: too much Th1 response, colon too acidic, too much IgG response to gut flora
--crohns: not enough cathelicidins (neutrophils)

ODD FACTS
MHC specific T cells have been isolated from humans
--specific for Th3/Tr1 phenotype, ie the ones that make TGFβ and IL-10
---->"immunosuppressive" environment in the gut
--Lamina propria cells (LPCs) may serve as APCs for oral tolerance-->present antigen-->IFNγ and TGFβ
B CELLS
--dietary antigen is present in blood inside 1 hour after ingestion
--low levels of IgM, IgG, and IgA specific for dietary antigens are found in sera and secretions

Th17 RESPONSE
--most recently discovered subset of T cells
--found in Psoriasis, Rheumatoid Arthritis, and other inflammatory diseases.
--originally thought to be involved in autoimmunity; now thought to be more involved in inflammation
--distinguished by their ability to produce IL-17, but NOT IL-4 or IFNg
--made when DCs/Macs are not making IL-12 or IL-4
--made when both IL-6 and TGFb are present
--express receptors for IL-23 (causes increased division but may not be the initiating cytokine)
--fungus can stimulate production of IL-23 instead of IL-12
--IL-17 stimulates neutrophils
--IL-17 regulates the production of many chemokines (i.e. cells don’t traffic properly in absence of IL-17)
--HIV patients are deficient in Th17 cells

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