Dendritic cells initiate early autoimmunity in the absence of functional regulatory T cells (115.7)

Abstract

BALB/c IL-2-KO mice develop systemic autoimmunity, dying within 4 wks from autoimmune hemolytic anemia. Disease in these mice is Th1-mediated, and IFNγ production is required for early autoimmunity. We asked whether APC are required for IFNγ production by T cells in the IL-2-KO mouse. Our data show that APC:T cell interactions through B7, but not via B cells, are necessary for IFNγ production in the absence of IL-2, suggesting that dendritic cells (DC) mediate this alteration. Disease is marked by DC accumulation, activation and elevated cytokine production, including IL-12 and type1-interferons. The depletion of either conventional (cDC) or plasmacytoid (pDC) significantly augmented the survival of IL-2-KO mice, demonstrating that DC contribute to the progression of autoimmunity. In the absence of IL-12, T cell activation and disease is only moderately altered, thus Th1 differentiation and IFNγ induction as a part of the underlying kinetics of autoimmunity is primarily IL-12-independent. Elimination of type 1 interferon signals in addition to IL-12 further augmented survival, indicating that cytokines derived from both pDC and cDC contribute to disease severity. Enhanced DC function is not dependent on T cell activation as DC in an environment without overt T cell activation are still functionally activated. Overall, our data suggest that DC activation can be an initiating event during the development of disease and thus DC are critical regulators of autoimmune development.