CD4+CD40+ T cells (Th40) drive a rapid and severe form of experimental autoimmune encephalomyelitis (BA11P.123)

Abstract

Abstract The CD40-CD154 dyad is critically involved in autoimmune diseases including Multiple Sclerosis (MS) and Type 1 Diabetes (T1D). CD4+CD40+ T cells, Th40, are necessary and sufficient to establish T1D in the mouse model. In the Experimental Autoimmune Encephalomyelitis (EAE) mouse model of MS, CD4 T cells are known to play a dominant role in disease development, however, the contribution of Th40 cells has not been determined. Here we reveal that the EAE induction regimen, specifically the Freund’s adjuvant (CFA), causes a significant expansion of Th40 cells, which in turn play a major role in EAE development. While expansion of Th40 cells is not dependent on specific antigen, the precipitation of central nervous system disease symptoms is MOG-antigen dependent, shaping a different TCR repertoire. We show that surface expression of CD40 on T cells is associated with a more rapid and severe disease course. Th40 cells are present in lesions in the brains and spinal cords of EAE mice and their cytokine profile is skewed toward IFNγ. In EAE facilitated by CD4+CD40- T cells, where disease develops with significantly slower kinetics and lesser severity, the cytokine profile is skewed more towards IL-17. Primary Th40 cells can adoptively transfer EAE, without prior in-vitro expansion, requiring only the injection of CFA in the recipient mice. These data demonstrate the importance of T cell CD40 and its relation to differential expression of IFNγ and IL-17 in EAE disease induction.