Th17 helper cells produce the pro-inflammatory cytokine IL-17 and are pathogenic in multiple sclerosis and its experimental model EAE. In vitro activation of naive CD4+T cells in presence of TGF?l induces regulatory T (Treg) cells;IL-6 addition to this induces Th17 cells while inhibiting Treg induction. Thus a reciprocal dichotomy controlled by IL-6 exists between Th17 and Treg induction. We will further investigate this mechanism in vivo. IL-23 plays a crucial role in Th17 development. In vitro assays show IL-23 maintains differentiated Th17 cells. Whether this role is true in vivo is not known and we will investigate this. To address these questions we will utilize (1) TGF?Tg - transgenic mice which express TGF?l only in T cells upon stimulation and show increased numbers of Th17 cells upon immunization, (2) Foxp3KI mice- express GFP from the Foxp3 locus, expression of Foxp3 is specific to Tregs and (3) MHC tetramers to detect antigen specific (tetramer*) cells. We now know EAE resistance in IL-6 deficient mice arises as a result of increased Tregs because deletion of Tregs makes IL-6 deficient mice susceptible to EAE.
Aim 1. To investigate reciprocal dichotomy between Treg and Th17 cells in vivo by using TGF?Tg mice in absence of IL-6->lf as demonstrated in vitro TGF? produces Treg cells in absence of IL-6 then we will see an increase in Treg cells in these mice in comparison to IL-6KO mice. Immunized Foxp3KI-TGFpTg-6KO mice will be examined for an increase in tetramer+ GFP+ cells in comparison to Foxp3KI-6KO mice. Function of Treg cells from Foxp3KI-TGF?Tg-6KO mice will be assessed in vitro and in vivo. Impact of this dichotomy on EAE will be examined. Treg cells will be deleted in these mice and examined for susceptibility to EAE.
Aim 2 : To determine role of IL-23 in both maintenance of Th17 cells in vivo and on generation of Treg cell-"""""""" IL-23 KO mice show Th17 cell deficiency upon immunization. Since TGF?Tg mice show increased numbers of Th17 cells we will follow their kinetics in IL-23 absence (TGF?Tg-IL23KO mice) and determine survival/maintenance of these cells. Foxp3KI-IL23KO mice will be used to determine if EAE resistance in IL-23 KO mice is also a result of increased tetramer+ GFP+ cells.

Public Health Relevance

The objective of our research is to understand mechanisms controlling the generation and balance of Th17 cells and Treg cells in vivo. Th17 cells are important in accelerating autoimmune disorders whereas T cells are important for slowing down disease. Understanding the mechanisms of this balance, which ultimately decides disease course in multiple sclerosis and arthritis, will help contribute to development of better targeted stage specific therapies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F07-L (20))
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Prograis, Lawrence J
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Brigham and Women's Hospital
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Mittal, Akanksha; Murugaiyan, Gopal; Beynon, Vanessa et al. (2012) IL-27 induction of IL-21 from human CD8+ T cells induces granzyme B in an autocrine manner. Immunol Cell Biol 90:831-5
Murugaiyan, Gopal; Mittal, Akanksha; Weiner, Howard L (2010) Identification of an IL-27/osteopontin axis in dendritic cells and its modulation by IFN-gamma limits IL-17-mediated autoimmune inflammation. Proc Natl Acad Sci U S A 107:11495-500
Murugaiyan, Gopal; Mittal, Akanksha; Lopez-Diego, Rocio et al. (2009) IL-27 is a key regulator of IL-10 and IL-17 production by human CD4+ T cells. J Immunol 183:2435-43
Murugaiyan, Gopal; Mittal, Akanksha; Weiner, Howard L (2008) Increased osteopontin expression in dendritic cells amplifies IL-17 production by CD4+ T cells in experimental autoimmune encephalomyelitis and in multiple sclerosis. J Immunol 181:7480-8