Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD
Tóm tắt
CD4+CD25+ regulatory T (Treg) cells are potent modulators of alloimmune responses. In murine models of allogeneic bone marrow transplantation, adoptive transfer of donor CD4+CD25+ Treg cells protects recipient mice from lethal acute graft-versus-host disease (aGVHD) induced by donor CD4+CD25- T cells. Here we examined the differential effect of CD62L+ and CD62L- subsets of CD4+CD25+ Treg cells on aGVHD-related mortality. Both subpopulations showed the characteristic features of CD4+CD25+ Treg cells in vitro and did not induce aGVHD in vivo. However, in cotransfer with donor CD4+CD25- T cells, only the CD62L+ subset of CD4+CD25+ Treg cells prevented severe tissue damage to the colon and protected recipients from lethal aGVHD. Early after transplantation, a higher number of donor-type Treg cells accumulated in host mesenteric lymph node (LN) and spleen when CD4+CD25+CD62L+ Treg cells were transferred compared with the CD62L- subset. Subsequently, CD4+CD25+CD62L+ Treg cells showed a significantly higher capacity than their CD62L- counterpart to inhibit the expansion of donor CD4+CD25- T cells. The ability of Treg cells to efficiently enter the priming sites of pathogenic allo-reactive T cells appears to be a prerequisite for their protective function in aGVHD.
Tài liệu tham khảo
Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus- host disease after allogeneic bone marrow transplantation. J Exp Med. 2002;196: 389-399.
Taylor PA, Lees CJ, Blazar BR. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood. 2002;99: 3493-3499.
Cohen JL, Trenado A, Vasey D, Klatzmann D, Salomon BL. CD4(+)CD25(+) immunoregulatory T cells: new therapeutics for graft-versus-host disease. J Exp Med. 2002;196: 401-406.
Edinger M, Hoffmann P, Ermann J, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. 2003;9: 1144-1150.
Trenado A, Charlotte F, Fisson S, et al. Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia. J Clin Invest. 2003;112: 1688-1696.
Jones SC, Murphy GF, Korngold R. Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD425 T cells to allow an effective graft-versus-leukemia response. Biol Blood Marrow Transplant. 2003;9: 243-256.
Butcher EC, Picker LJ. Lymphocyte homing and homeostasis. Science. 1996;272: 60-66.
Anderson BE, McNiff J, Yan J, et al. Memory CD4+ T cells do not induce graft-versus-host disease. J Clin Invest. 2003;112: 101-108.
Chen BJ, Cui X, Sempowski GD, Liu C, Chao NJ. Transfer of allogeneic CD62L-memory T cells without graft-versus-host disease. Blood. Prepublished on October 9, 2003, as DOI 10.1182/blood-2003-08-2987. (Now available as Blood. 2004; 103: 1534-1541).
Kuniyasu Y, Takahashi T, Itoh M, Shimizu J, Toda G, Sakaguchi S. Naturally anergic and suppressive CD25(+)CD4(+) T cells as a functionally and phenotypically distinct immunoregulatory T cell subpopulation. Int Immunol. 2000;12: 1145-1155.
Thornton AM, Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol. 2000;164: 183-190.
Szanya V, Ermann J, Taylor C, Holness C, Fathman CG. The subpopulation of CD4(+)CD25(+) splenocytes that delays adoptive transfer of diabetes expresses L-selectin and high levels of CCR7. J Immunol. 2002;169: 2461-2465.
Fu S, Yopp AC, Mao X, et al. CD4+ CD25+ CD62L+ T-regulatory cell subset has optimal suppressive and proliferative potential. Am J Transplant. 2004;4: 65-78.
Ridolfi R, Riccobon A, Galassi R, et al. Evaluation of in vivo labelled dendritic cell migration in cancer patients. J Transl Med. 2004;2: 27.
Eberl G, MacDonald HR. Rapid death and regeneration of NKT cells in anti-CD3epsilon- or IL-12-treated mice: a major role for bone marrow in NKT cell homeostasis. Immunity. 1998;9: 345-353.
Ermann J, Szanya V, Ford GS, Paragas V, Fathman CG, Lejon K. Cd4(+)cd25(+) T cells facilitate the induction of T cell anergy. J Immunol. 2001;167: 4271-4275.
McHugh RS, Whitters MJ, Piccirillo CA, et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity. 2002;16: 311-323.
Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol. 2002;3: 135-142.
Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4: 330-336.
Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299: 1057-1061.
Lan F, Zeng D, Huie P, Higgins JP, Strober S. Allogeneic bone marrow cells that facilitate complete chimerism and eliminate tumor cells express both CD8 and T-cell antigen receptor-alphabeta. Blood. 2001;97: 3458-3465.
Ferrara J. Location, location, location. Nat Immunol. 2003;4: 103-104.
M'Rini C, Cheng G, Schweitzer C, et al. A novel endothelial L-selectin ligand activity in lymph node medulla that is regulated by alpha(1,3)-fucosyltransferase-IV. J Exp Med. 2003;198: 1301-1312.
Li B, New JY, Yap EH, Lu J, Chan SH, Hu H. Blocking L-selectin and alpha4-integrin changes donor cell homing pattern and ameliorates murine acute graft versus host disease. Eur J Immunol. 2001;31: 617-624.
Li B, New JY, Tay YK, et al. Delaying acute graft-versus-host disease in mouse bone marrow transplantation by treating donor cells with antibodies directed at l-selectin and alpha4-integrin prior to infusion. Scand J Immunol. 2004;59: 464-468.
Bradley LM, Duncan DD, Tonkonogy S, Swain SL. Characterization of antigen-specific CD4+ effector T cells in vivo: immunization results in a transient population of MEL-14-, CD45RB-helper cells that secretes interleukin 2 (IL-2), IL-3, IL-4, and interferon gamma. J Exp Med. 1991;174: 547-559.
Walker LS, Chodos A, Eggena M, Dooms H, Abbas AK. Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J Exp Med. 2003;198: 249-258.
Apostolou I, Sarukhan A, Klein L, von Boehmer H. Origin of regulatory T cells with known specificity for antigen. Nat Immunol. 2002;3: 756-763.
Thornton AM, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med. 1998;188: 287-296.
Fisson S, Darrasse-Jeze G, Litvinova E, et al. Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J Exp Med. 2003;198: 737-746.