Regulatory functions of self-restricted MHC class II allopeptide-specific Th2 clones in vivo

We studied T-cell clones generated from grafts of rejecting and tolerant an imals and investigated the regulatory function of Th2 clones in vitro and i n vivo. To prevent allograft rejection, we treated LEW strain recipient rat s of WF strain kidney grafts with CTLA4Ig to block CD28-B7 costimulation. W e then isolated epitope-specific T-cell clones from the engrafted tissue, u sing a donor-derived immunodominant class II MHC allopepride presented by r ecipient antigen-presenting cells. Acutely rejected tissue from untreated a nimals yielded self-restricted, allopeptide-specific T-cell clones that pro duced IFN-gamma, whereas clones from tolerant animals produced IL-4 and IL- 10. Adoptive transfer into naive recipients of Th1 clones, but not Th2 clon es, induced alloantigen-specific delayed-type hypersensitivity (DTH) respon ses. In addition, Th2 clones suppressed DTH responses mediated by Th1 clone s in vivo and blocked Th1 cell proliferation and IFN-gamma production in vi tro, A pilot human study showed that HLA-DR allopeptide-specific T-cell clo nes generated from patients with chronic rejection secrete Th1 cytokines, w hereas those from patients with stable graft function produce Th2 cytokines in response to donor-specific HLA-DR allopeptides. We suggest that self-re stricted alloantigen-specific Th2 clones may regulate the alloimmune respon ses and promote long-term allograft survival and tolerance.