Direct recognition of hepatocyte-expressed MHC class I alloantigens is required for tolerance induction

Abstract

Adeno-associated viral vector-mediated (AAV-mediated) expression of allogeneic major histocompatibility complex class I (MHC class I) in recipient liver induces donor-specific tolerance in mouse skin transplant models in which a class I allele (H-2Kb or H-2Kd) is mismatched between donor and recipient. Tolerance can be induced in mice primed by prior rejection of a donor-strain skin graft, as well as in naive recipients. Allogeneic MHC class I may be recognized by recipient T cells as an intact molecule (direct recognition) or may be processed and presented as an allogeneic peptide in the context of self-MHC (indirect recognition). The relative contributions of direct and indirect allorecognition to tolerance induction in this setting are unknown. Using hepatocyte-specific AAV vectors encoding WT allogeneic MHC class I molecules, or class I molecules containing a point mutation (D227K) that impedes direct recognition of intact allogeneic MHC class I by CD8+ T cells without hampering the presentation of processed peptides derived from allogeneic MHC class I, we show here that tolerance induction depends upon recognition of intact MHC class I. Indirect recognition alone yielded a modest prolongation of subsequent skin graft survival, attributable to the generation of CD4+ Tregs, but it was not sufficient to induce tolerance.

Role of Regulatory T Cell and Effector T Cell Exhaustion in Liver-Mediated Transgene Tolerance in Muscle

“…Here, we show the control of an already established CD8 + T cell response against hSGCA mediated by both the induction of Tregs and the homing of transgene-specific CD8 + T cells to the liver, where they express PD-1 and LAG3. The exact mechanism driving homing of reactive CD8 + T cells to the liver remains to be elucidated, although recent work from Paul-Heng and colleagues 49 suggests that direct recognition of antigen expressed in the liver by CD8 + T cells via MHC class I is a key mediator of liver tolerance. Thus, it is conceivable that homing of reactive CD8 + T cells to the liver, via MHC class I recognition of the expressed transgene, together with the unique protolerogenic hepatic immune environment, results in the control of cytotoxic responses via T cell exhaustion.…”

Dual muscle-liver transduction imposes immune tolerance for muscle transgene engraftment despite preexisting immunity

“…Likewise, studies performed by Kumar et al (35) and Tay et al (34) showed that low transgene expression in the liver and high avidity of the T cell for the transgene (34) leads to T cell activation after adoptive transfer of transgenic, OVA-specific CD8 + T cells. Along this line, Paul-Heng et al have recently demonstrated in C57BL/6 mice that high liver expression of an intact allogenic MHCI H2-K d molecule allows indefinite survival of an allogenic H2-K d skin graft (27), whereas liver expression of a mutated H2-K d -D227K transgene, which abrogates recognition of intact allogenic MHCI by CD8 + T cells, leads to partial skin graft survival. Consistent with our results, these studies indicate that liver transgene doses and interaction modalities of transgene-specific CD8 + T cells with transduced hepatocytes are critical for their fate.…”

“…These features are specific to the combination of transgene and mouse strain under consideration and likely explain differences observed in the literature regarding the potency of liver tolerance examined with different transgenes and mouse strains (31,47). Of importance, Paul-Heng et al showed that direct recognition of hepatocyte-expressed MHCI allogenic antigens is required for tolerance induction and skin engraftment (27). Our results demonstrate that processing of a defined muscle transgene by antigen-presenting cells of the host leads to CD8 + T cell responses, which are tolerized after recognition of hepatocyte-expressed host MHCI transgene complexes, even in presence of preexisting immunity.…”

“…As for harnessing the tolerogenic properties of the liver, reports showed that expression of an allogenic MHC component in the liver allowed successful engraftment of a transgenic skin graft bearing the same allogenic MHC antigen (26,27). Likewise, rAAV-mediated liver targeting proved safe and efficient in hemophilia mouse models with a human FIX transgene or using a variety of transgenes and rAAV serotypes (28)(29)(30).…”

Mechanisms of Immune Tolerance in Liver Transplantation-Crosstalk Between Alloreactive T Cells and Liver Cells With Therapeutic Prospects

“…However, low expression of co-stimulatory molecules on hepatocytes leads to apoptosis of the alloreactive T cells (10). Paul-Heng et al have found that direct recognition of hepatocyte expressed MHC-I alloantigen (cross presentation) is required for tolerance induction, whereas the indirect recognition of the processed and presented allogeneic peptide on MHC-II by CD4 T cells is not sufficient for tolerance induction although it can prolong the graft survival and generate Tregs to promote transplant tolerance (78, 79). Additionally, processing of the soluble antigens into peptide presented by MHC-I is impaired in hepatocytes lacking collectrin, which is an intracellular chaperone protein within the endoplasmic reticulum-Golgi intermediate compartment and positively regulated (80).…”