Intracellular MHC Class II Controls Regulatory Tolerance to Allogeneic Transplants

Abstract

MHC class II (MHCII) genes have been implicated in the regulation of T lymphocyte responses. However, the mechanism of MHCII-driven regulation remains unknown. Matching for MHCII between donors and recipients of allografts favors regulatory T cell tolerance to transplants and provides a unique opportunity to study this regulation. In this study, we investigated MHCII regulation using transfer of donor MHCII genes in recipients of cardiac allografts. Transfer of MHCII IAb genes in the bone marrow of CBA mice (H-2k) prior to the grafting of IAb+ fully allogeneic C57BL/6 (B6, H-2b) heart transplants resulted in donor-specific tolerance associated with long-term survival of B6, but not third-party, allografts without sustained immunosuppression. Strikingly, the majority of accepted heart transplants (>170 d) were devoid of allograft vasculopathy. Further studies indicated that intracellular IAb initiated the tolerogenic process, which was mediated by regulatory T cells (Tregs) that polarized antigraft responses to Th2 cytokine producers. This mechanism seems to be unique to MHCII genes, because previous MHC class I gene-based therapies failed to produce Tregs. These results demonstrate the key role of MHCII in the induction of Tregs. They also underscore a potential mechanism of specific inactivation of T cells in this model; when activated by IAb+ grafts, IAb-specific Tregs repress the entire alloresponse to C57BL/6 transplants (including MHC I and minor Ags), thus mediating T cell tolerance.

Contributions of Direct and Indirect Alloresponses to Chronic Rejection of Kidney Allografts in Nonhuman Primates

“…Most importantly, in some monkeys, this direct response was associated with the production of donor-specific alloantibodies presumably due to T-B cognate interactions rendered possible by sharing of MHC class II genes between donor and recipients and it correlated with the presence of chronic allograft rejection of kidney-transplants. This suggests that while MHC class II gene matching between donor and recpients is likely to reduce the risk of acute rejection and presumably favor the activation/expansion of some Tregs (53, 54), it could increase the risk of chronic rejection.…”

Allorecognition by T Lymphocytes and Allograft Rejection

“…Studies from LeGuern’s laboratory suggest that tTreg recognition is biased to self-MHC class II peptides bound with self-MHC class II molecules themselves (referred to as Tlo) (108). Tolerance of solid organ transplants in swine and rodents via allo-MHC class II transgenesis support this view (109–113). In contrast to tTregs, pTregs presumably acquire FoxP3 expression and suppressor functions through recognition of donor antigens (MHC and/or minor antigens) presented by selected APCs (immature DCs and plasmocytoid DCs) in an appropriate cytokine milieu (4, 114–117).…”

α-1 Antitrypsin Promotes Semimature, IL-10–Producing and Readily Migrating Tolerogenic Dendritic Cells

“…11); smDC also produce high levels of 13). Whereas this profile might appear to render the cells less than optimal APCs, their ability to migrate to the DLN is suggested to be preserved (5).…”