Viral IL-10-induced immunosuppression requires Th2 cytokines and impairs APC function within the allograft

Previous reports demonstrated that retroviral mediated gene transfer of vir al IL-10 (vIL-10) prolongs allograft survival by decreasing donor-specific cytotoxic T lymphocyte precursor (CTLp) and IL-2-secreting helper T Iymphoc yte precursor (HTLp) frequency within graft-infiltrating cells (GIC), This report now shows that vIL-10 efficacy is dependent on CD4(+) T cells, sugge sting that immunosuppression may involve a snitch from a Th1 to a Th2 allor esponse, In support of this, anti-IL-4 or anti-murine LL-IO (anti-mIL-10) m Abs, but not anti-IFN-gamma mAb, administered at the time of vIL-10 gene tr ansfer prevents enhanced graft survival, Because Th switching involves APC function, GIC were examined for their ability to present alloantigen, GIC f rom vIL-10-treated grafts were shown to be mostly of recipient (CBA) origin , yet were unable to elicit alloproliferative responses from donor type (C5 7BL/6) or third party (BALB/c) responders. The inability of vIL-10-treated GIC to stimulate the MLR,vas not due to the generation of negative regulato ry cells or the production of immunosuppressive cytokines such as IL-4, mIL -10, or TGF beta. Using fractionated GIC subpopulations, the number of reci pient type cells in the allografts was modestly reduced by vIL-10 gene tran sfer, while maintaining both APC phenotype and alloantigen presenting funct ion. Conversely, after vIL-10 gene transfer, donor type GIC were unable to participate in direct alloantigen presentation. Therefore, local immunosupp ression induced by vIL-10 gene transfer is CD4 T cell and IL-4 and mIL-10 d ependent, and impairs direct alloantigen presentation through an alteration of donor type APC function.