Th1 or Th17 cells: What are the pathogenic T cells in CNS autoimmunity?

Th1 or Th17 cells: What are the pathogenic T cells in CNS autoimmunity?

Thursday, March 22, 2007

The New York Academy of Sciences

Organizer: Vijay K. Kuchroo, Harvard Medical School

Speakers: Vijay K. Kuchroo, Harvard Medical School; Daniel Cua, Schering-Plough; Laurie Harrington, University of Alabama; Daniel Littman, Skirball Institute, NYU

 

Abstracts

Induction of CNS Autoimmunity by Th1 and Th17 cells.
Vijay K. Kuchroo, DVM, PhD
Center for Neurologic Diseases, Brigham and Women's Hospital

Upon activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (TH) cells are traditionally thought to differentiate into TH1 and TH2 cell subsets. TH1 cells are necessary to clear intracellular pathogens and TH2 cells are important for clearing extracellular organisms. Recently, a subset of interleukin (IL)-17-producing T cells (TH17) distinct from TH1 or TH2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury including Rheumatoid Arthritis (RA). Although a number of studies have previously described that Th1 cells are the pathogenic T cells, but the recent discovery of Th17 cells has questioned whether Th1 cells are indeed pathogenic or whether Th17 cells are the only subset capable of inducing autoimmunity. In contrast to the auto- pathogenic, CD4+CD25+, Fox-P3+ regulatory T cells (T-regs) inhibit autoimmunity and protect against tissue injury. TGF-β1 is a critical differentiation factor for the generation of T-regs and using Foxp3-GFP "knock-in" mice we show that IL-6, an acute phase protein induced during inflammation, completely inhibits the generation of Foxp3+ T-reg cells induced by TGF-β1. On the other hand, we demonstrate that IL-23 is not the differentiation factor for the generation Th-IL-17 cells, instead IL-6 and TGF-β1 induces differentiation of pathogenic Th-IL-17 T cells from naïve T cells. Consistent with this observation, immunization of inducible TGF-β1 transgenic mice with myelin antigens in complete Freund's adjuvant induces a severe and lethal experimental autoimmune encephalomyelitis (EAE) with massive production of IL-17. Our data demonstrate a dichotomy in the generation of pathogenic (Th-IL-17) T cells that induce autoimmunity and regulatory (Foxp3+) T cells that inhibit autoimmune tissue injury. Furthermore, we show that the CD4+,CD25+ T cells accumulate in the target tissue during autoimmune inflammation but does not suppress ongoing tissue inflammation because of resistance of effector T cells to suppression. We will discuss this data in the context of autoimmune diseases like RA where there may be enrichment of CD4+,CD25+ T-reg cells in the affected joint yet they are not able to inhibit progression of disease.

Effector CD4 T cells during chronic inflammation: trust your gut
Laurie Harrington
University of Alabama

Adaptive immune responses are critical for the control of pathogens, however these responses also mediate many autoimmune and chronic inflammatory diseases. A key component of the adaptive immune response is CD4 T cells and through their ability to secrete polarizing cytokines, these cells regulate adaptive immune responses and therefore mediate the initiation of chronic inflammatory disorders such as multiple sclerosis (MS) and inflammatory bowel disease (IBD).

Although immunopathology mediated by inappropriate or poorly controlled effector T cell responses has often been characterized as Th1-mediated, findings from a number of mouse models of chronic inflammation have highlighted the importance of IL-23-dependent IL-17-producing CD4 T cells in driving disease, not IL-12-induced IFNγ-producing cells. While the importance of IL-17-producing CD4 T cells in autoimmune pathogenesis has become increasingly evident, it is well established that Th1 effector CD4 T cells are elicited during chronic inflammation, however the significance of these cell populations, if not pathogenic, remains elusive. Provocative data fr