IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo.
We present evidence that donor-reactive CD4(+) T cells present in mice tolerant to donor alloantigens are phenotypically and functionally heterogeneous. CD4(+) T cells contained within the CD45RB(high) fraction remained capable of mediating graft rejection when transferred to donor alloantigen-grafted T cell-depleted mice. In contrast, the CD45RB(low) CD4(+) and CD25(+)CD4(+) populations failed to induce rejection, but rather, were able to inhibit rejection initiated by naive CD45RB(high) CD4(+) T cells. Analysis of the mechanism of immunoregulation transferred by CD45RB(low) CD4(+) T cells in vivo revealed that it was donor Ag specific and could be inhibited by neutralizing Abs reactive with IL-10, but not IL-4. CD45RB(low) CD4(+) T cells from tolerant mice were also immune suppressive in vitro, as coculture of these cells with naive CD45RB(high) CD4(+) T cells inhibited proliferation and Th1 cytokine production in response to donor alloantigens presented via the indirect pathway. These results demonstrate that alloantigen-specific regulatory T cells contained within the CD45RB(low) CD4(+) T cell population are responsible for the maintenance of tolerance to donor alloantigens in vivo and require IL-10 for functional activity.
Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
M
M
Hara
C I
CI
Kingsley
M
M
Niimi
S
S
Read
S E
SE
Turvey
A R
AR
Bushell
P J
PJ
Morris
F
F
Powrie
K J
KJ
Wood
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015704:CD4 Antigens / Q000096:biosynthesis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002469:Cell Separation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D007275:Injections, Intravenous; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D007399:Interphase / Q000276:immunology; D007519:Isoantigens / Q000008:administration & dosage / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D023001:Transplantation Tolerance / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016207:Cytokines; D007519:Isoantigens; D015375:Receptors, Interleukin-2; D016753:Interleukin-10; D015847:Interleukin-4; D017493:Leukocyte Common Antigens