A cellular analysis of CD4+ T cell in Autoimmune diseases

Abstract

Autoimmune diseases arise when the immune system recognizes and is activated by “self” antigens, leading to damage and destruction of organs and tissues. CD4+ T cells are essential for pathogenesis of autoimmune diseases because they play roles in immunological memory, thereby enabling the immune system to respond quickly if it re-encounters the antigen. I studied CD4+ T cell immune responses in two representative autoimmune diseases: rheumatoid arthritis (RA) and multiple sclerosis (MS). In Here, I used two animal models of these diseases: collagen-induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE). In part I, I examined BATF expression in CD4+ T cells invading the arthritic synovial tissues of CIA mice. additionally, BATF-deficient mice did not develop CIA, but K/BxN serum transfer did (the latter is a type of T cell-independent inflammatory arthritis). Previous studies suggest that BATF is closely related to T helper cells (Th) 17, which play key roles in the pathogenesis and symptoms of CIA. BATF-deficient mice with CIA showed decreased Th17 differentiation and reduced Th17 cell numbers. BATF deficiency reduced the numbers of Foxp3+ interleukin (IL)-17a+ CD4+ T cells, which are pathogenic Thus, BATF signaling in CD4+ T cells is essential for CIA symptoms. In part II, I examined newly-identified Notch2+ CD4+ T cells present in the spinal cord of EAE mice. Notch2+ CD4+ T cells were less inflammatory than Notch2+ CD4+ T cells, also Notch2+ CD4+ T cells expressed intermediate levels of Foxp3 (Foxp3int) depending on the degree of EAE progression. Although Notch2+ CD4+ T cells had an exhausted phenotype, Foxp3int Notch2+ CD4+ T cells exerted immunoregulatory functions both in in vitro and in vivo. Additionally, I examined whether Notch signaling affects expression of Foxp3. The results show that Jag1-Notch signaling maintains expression of Foxp3 after TCR stimulation. Collectively, the results suggest that Notch2 signaling in CD4+ T cells plays an important role in autoimmunity, and point to a new therapeutic target for MS.