title: SHIP limits immunoregulatory capacity in the T-cell compartment.
abstract: Regulatory T cells (T(regs)) play a pivotal role in preventing autoimmunity, graft-versus-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(+) T(regs) 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 FcgammaRII/III expression. SHIP deficiency does not compromise T(reg) function because SHIP-deficient CD3(+)CD4(+)CD25(+) T(regs) are as suppressive as wild-type (WT) CD3(+)CD4(+)CD25(+) T(reg). Interestingly, like conventional T(regs), 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.
authors.affiliation: Department of Immunology, Moffitt Comprehensive Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Collazo
authors.forename: Daniela
authors.initials: D
authors.lastname: Wood
authors.forename: Kim H T
authors.initials: KH
authors.lastname: Paraiso
authors.forename: Erin
authors.initials: E
authors.lastname: Lund
authors.forename: Robert W
authors.initials: RW
authors.lastname: Engelman
authors.forename: Cam-Tien
authors.initials: CT
authors.lastname: Le
authors.forename: Diana
authors.initials: D
authors.lastname: Stauch
authors.forename: Katja
authors.initials: K
authors.lastname: Kotsch
authors.forename: William G
authors.initials: WG
authors.lastname: Kerr
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D000072181:Inositol Polyphosphate 5-Phosphatases; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D014184:Transplantation, Homologous
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases