Role of T Cell TGFβ Signaling and IL-17 in Allograft Acceptance and Fibrosis Associated with Chronic Rejection

Chronic allograft rejection (CR) is the main barrier to long-term transplant survival. CR is a progressive disease defined by interstitial fibrosis, vascular neointimal development, and graft dysfunction. The underlying mechanisms responsible for CR remain poorly defined. TGF beta has been implicated in promoting fibrotic diseases including CR, but is beneficial in the transplant setting due to its immunosuppressive activity. To assess the requirement for T cell TGF beta signaling in allograft acceptance and the progression of CR, we used mice with abrogated T cell TGF beta signaling as allograft recipients. We compared responses from recipients that were transiently depleted of CD4(+) cells (that develop CR and express intragraft TGF beta) with responses from mice that received anti-CD40L mAb therapy (that do not develop CR and do not express intragraft TGF beta). Allograft acceptance and suppression of graft-reactive T and B cells were independent of T cell TGF beta signaling in mice treated with anti-CD40L mAb. In recipients transiently depleted of CD4(+) T cells, T cell TGF beta signaling was required for the development of fibrosis associated with CR, long-term graft acceptance, and suppression of graft-reactive T and B cell responses. Furthermore, IL-17 was identified as a critical element in TGF beta-driven allograft fibrosis. Thus, IL-17 may provide a therapeutic target for preventing graft fibrosis, a measure of CR, while sparing the immunosuppressive activity of TGF beta. The Journal of Immunology, 2009, 183: 7297-7306.