SHIP limits immunoregulatory capacity in the T-cell compartment

Abstract

Regulatory T cells (Tregs) play a pivotal role in preventing autoimmunity, graftversus-host disease (GVHD), and organ graft rejection. We previously showed that either germline or induced SH2 domain-containing inositol 5-phosphatase (SHIP) deficiency in the host abrogates GVHD. Here we show that SHIP deficiency promotes an increase of CD4+CD25 +FoxP3+ Tregs and CD4+CD25- FoxP3+"naive" T cells in the periphery that display increased CD103, glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR), OX40, and FcγRII/III expression. SHIP deficiency does not compromise Treg function because SHIP-deficient CD3 +CD4+CD25+ Tregs are as suppressive as wild-type (WT) CD3+CD4+CD25+ T reg. Interestingly, like conventional Tregs, SHIP-/- CD4+CD25-T cells are unresponsive to major histocompatibility complex (MHC)-mismatched stimulators and suppress allogeneic responses by T cells in vitro. In addition, SHIP-/- CD4+CD25 -T cells mediate reduced lethal GVHD on adoptive transfer to MHC-mismatched hosts. Furthermore, hosts with induced SHIP deficiency exhibit delayed rejection of MHC-mismatched cardiac grafts. Thus, SHIP is required for robust graft-versus-host and host-versus-graft responses by CD4+ T cell and limits their immunoregulatory capacity. These findings further define the immunosuppressive mechanisms that result from SHIP deficiency and provide additional justification for targeting SHIP in clinical transplantation. © 2009 by The American Society of Hematology.