Invariant NKT Cells Promote the Development of Highly Cytotoxic Multipotent CXCR3+CCR4+CD8+ T Cells That Mediate Rapid Hepatocyte Allograft Rejection

Hepatocyte transplant represents a treatment for metabolic disorders but is limited by immunogenicity. Our prior work identified the critical role of CD8(+) T cells, with or without CD4(+) T cell help, in mediating hepatocyte rejection. In this study, we evaluated the influence of invariant NKT (iNKT) cells, uniquely abundant in the liver, upon CD8-mediated immune responses in the presence and absence of CD4(+) T cells. To investigate this, C57BL/6 (wild-type) and iNKT-deficient J alpha 18 knockout mice (cohorts CD4 depleted) were transplanted with allogeneic hepatocytes. Recipients were evaluated for alloprimed CD8(+) T cell subset composition, allocytotoxicity, and hepatocyte rejection. We found that CD8-mediated allocytotoxicity was significantly decreased in iNKT-deficient recipients and was restored by adoptive transfer of iNKT cells. In the absence of both iNKT cells and CD4(+) T cells, CD8-mediated allocytotoxicity and hepatocyte rejection was abrogated. iNKT cells enhance the proportion of a novel subset of multipotent, alloprimed CXCR3(+)CCR4(+)CD8(+) cytolytic T cells that develop after hepatocyte transplant and are abundant in the liver. Alloprimed CXCR3(+)CCR4(+)CD8(+) T cells express cytotoxic effector molecules (perforin/granzyme and Fas ligand) and are distinguished from alloprimed CXCR3(+)CCR42CD8(+) T cells by a higher proportion of cells expressing TNF-alpha and IFN-gamma. Furthermore, alloprimed CXCR3(+)CCR4(+)CD8(+) T cells mediate higher allocytotoxicity and more rapid allograft rejection. Our data demonstrate the important role of iNKT cells in promoting the development of highly cytotoxic, multipotent CXCR3(+)CCR4(+)CD8(+) T cells that mediate rapid rejection of allogeneic hepatocytes engrafted in the liver. Targeting iNKT cells may be an efficacious therapy to prevent rejection of intrahepatic cellular transplants.

Automated summary

iNKT cells play a crucial role in modulating CD8-mediated immune responses in the presence or absence of CD4(+) T cells. Lack of iNKT cells decreases CD8-mediated allocytotoxicity, which can be restored by adoptive transfer of iNKT cells. including TNF-alpha and IFN-gamma.