SHIP limits immunoregulatory capacity in the T-cell compartment

• Published in: Blood Vol. 113; no. 13; pp. 2934 - 2944
• Main Authors: Collazo, Michelle M., Wood, Daniela, Paraiso, Kim H.T., Lund, Erin, Engelman, Robert W., Le, Cam-Tien, Stauch, Diana, Kotsch, Katja, Kerr, William G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26-03-2009; American Society of Hematology
• Series: Immunobiology
• Subjects: Adoptive Transfer; Animals; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - transplantation; Forkhead Transcription Factors - metabolism; Graft vs Host Disease - genetics; Graft vs Host Disease - immunology; Graft vs Host Disease - prevention & control; Immune Tolerance - genetics; Immune Tolerance - immunology; Immunobiology; Inositol Polyphosphate 5-Phosphatases; Interleukin-2 Receptor alpha Subunit - metabolism; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Lymphocyte Count; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, SCID; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; Phosphoric Monoester Hydrolases - physiology; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - transplantation; Transplantation, Homologous
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-09-181164

Regulatory T cells (Tregs) 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+ 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+ Treg. 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.