Depletion of Foxp3+ T Cells Abrogates Tolerance of Skin and Heart Allografts in Murine Mixed Chimeras Without the Loss of Mixed Chimerism

Abstract

The relative contribution of central and peripheral mechanisms to the generation and maintenance of allograft tolerance is of considerable interest. Here, we present new evidence that regulatory T cells (Foxp3+) maintain skin and heart allograft tolerance in mixed hematopoietic chimeric mice. Transient depletion of both donor‐ and recipient‐derived Foxp3+ cells was necessary and sufficient to induce decisive rejection of long‐accepted skin and heart allografts. In contrast, stable hematopoietic chimerism remained, and there was no detectable induction of donor‐specific reactivity to hematopoietic cells. Foxp3+ cell depletion did not result in the rejection of skin grafts of only MHC‐disparate donors (B6.C‐H2d/bByJ), indicating that MHC antigens were not the target in the graft. We conclude that two different mechanisms of tolerance are present in mixed chimeras. Hematopoietic chimerism, resistant to Foxp3+ depletion, is probably due to deletional tolerance to MHC antigens, as supported by previous studies. In contrast, regulatory tolerance mechanisms involving Foxp3+ cells are required to control reactivity against non‐MHC antigens not present on hematopoietic lineages.

Clonal Deletion Established via Invariant NKT Cell Activation and Costimulatory Blockade Requires In Vivo Expansion of Regulatory T Cells

“…þ Tregs were required to maintain skin-and cardiac-allograft tolerance even in the chimeras (34,35). However, this late-phase rejection was also observed even when whole CD4 þ T cells including CD4 þ CD25 þ Tregs were transferred into SCID mice (not shown).…”

Nonchimeric HLA-Identical Renal Transplant Tolerance: Regulatory Immunophenotypic/Genomic Biomarkers

“…HLA identity may be advantageously assessed, eliminating variability of immune response genes associated with donor/recipient specific HLA polymorphisms. Additionally, immunoregulation (Tregs) may be aided by self-recognition by the recipient of both donor major histocompatibility complexes (MHC) (12, 13). We described earlier in a brief communication (10) 3-year results of a tolerance protocol in 10 RT recipients HLA identical with their living donor siblings using 4 infusions of donor hematopoietic stem cells (DHSC).…”

Hematopoietic stem cell infusion/transplantation for induction of allograft tolerance

“…Uehara et al reported that skin and heart allografts accepted by mice displaying stable mixed chimerism later developed cardiac allograft vasculopathy (chronic rejection) dependent on the presence of host CD4 + T cells [24]. More recently, Shinoda et al found that depleting Foxp3 + T cells abrogated tolerance of skin and heart allografts in stable mixed chimeras without an associated loss of mixed chimerism [25]. Of note, the authors here found that host T cells collected from the rejecting mice were unable to mount a mixed lymphocyte reaction against donor cells.…”

“…The latter finding indicates that rejection in these animals was not mediated by T cells directed against intact allogeneic MHC molecules on donor APCs. In other words, it did not involve direct allorecognition [25]. Instead, it is likely that the T cells causing rejection were directed toward cryptic determinants on donor MHC, minor antigens, or graft tissue-specific antigens presented in an indirect fashion, as previously described [26-29].…”