Different Mechanisms Control Peripheral and Central Tolerance in Hematopoietic Chimeric Mice

Abstract

Regulatory T cells (Treg) are important in peripheral tolerance, but their role in establishing and maintaining hematopoietic mixed chimerism and generating central tolerance is unclear. We now show that costimulation blockade using a donor-specific transfusion and anti-CD154 antibody applied to mice given bone marrow and simultaneously transplanted with skin allografts leads to hematopoietic chimerism and permanent skin allograft survival. Chimeric mice bearing intact skin allografts fail to generate effector/memory T cells against allogeneic targets as shown by the absence of IFNc -producing CD44 high CD8 + T cells and in vivo cytotoxicity. Depletion of Tregs by injection of anti-CD4 or anti-CD25 antibody prior to costimulation blockade prevents chimerism, shortens skin allograft survival and leads to generation of effector/memory cytotoxic T cells. Depletion of Tregs by injection of anti-CD4 or anti-CD25 antibody two months after transplantation leads to loss of skin allografts even though mice remain chimeric and exhibit little in vivo cytotoxicity. In contrast, chimerism is lost, but skin allografts survive following naïve T-cell injection. We conclude that hematopoietic chimerism and peripheral tolerance may be maintained by different mechanisms in mixed hematopoietic chimeras.

Contribution of Regulatory T Cells and Effector T Cell Deletion in Tolerance Induction by Costimulation Blockadel

“…Whether the increased percentage of Foxp3-positive donor CD4 ϩ cells is derived from preexisting nTreg or due to de novo induction of adaptive Treg is at present unknown. Several studies have already suggested that the result of costimulation blockade is at least partially based on the induction of Treg (33)(34)(35). We previously demonstrated that human T cell activation by costimulatory signaldeficient allogeneic cells induces anergic T cells with regulatory activity (36).…”

A Novel Approach Inducing Transplant Tolerance By Activated Invariant Natural Killer T Cells With Co-Stimulatory Blockade.

“…In those studies, the impact of Treg-depletion might be insufficient to induce allogeneic hematopoietic cell rejection because they used stronger immune suppression or lower immunological barrier models than ours. Other supportive studies described the abrogation of mixed chimerism induction with anti-CD25 mAb in the lower invasive protocol setting of fully-allo combination (27,51). It is presumable that there is a delicate balance between Tregs and effector T cells (Teffs) in allograft tolerance.…”

Immunological Considerations for Inducing Skin Graft Tolerance

“…Skin grafts Autoimmunity (Oderup et al, 2006) Il2Rbeta-/-recipients Heart (Oderup et al, 2006) Rag 1 -/-given anti-154 and anti-B7 Chimerism (Iudaev et al, 1975) Sublethal WBI and BMC Hy antigen and HVG (Weng et al, 2007) Sublethal WBI Chimerism Skin allografts (Yamazaki et al, 2007) BMC, DST and anti-CD154…”