Autoreactive CD4+ Th1 cells activate monocytes to support Th17 responses in inflammatory arthritis (60.8)

Abstract

Abstract Th17 cells have been implicated in a number of autoimmune and inflammatory disorders, yet signals that can lead to a Th17 response in vivo are poorly understood. We have analyzed this question using a transgenic mouse model in which autoreactive CD4+ T cells recognizing a ubiquitously expressed surrogate self-antigen (influenza HA) induce inflammatory arthritis by an IL-17-dependent mechanism. Arthritis development is accompanied by an accumulation in the joint draining lymph nodes of inflammatory monocytes (iMOs) that have an enhanced capacity to support Th17 responses in vitro. The accumulation of iMOs in the LNs is preceded by an autoreactive CD4+ Th1 cell response, and by the upregulation of MHCII on iMOs in the spleens of pre-arthritic mice. Adoptive transfer of HA-specific CD4+ T cells into mice that expressed HA as a self-antigen similarly led to the formation of Th1 cells and of MHCII+ iMO that could support Th17 cell formation in vitro, and significantly, the accumulation of these iMOs in the LNs was blocked by IFNγ neutralization. Collectively, these studies provide a basis by which autoreactive CD4+ Th1 cells directed to a systemically distributed self-antigen can promote a regional inflammatory disease (arthritis) by promoting the formation of Th17-trophic iMO and driving their recruitment into the LNs.