期刊
JOURNAL OF IMMUNOLOGY
卷 207, 期 12, 页码 3107-3121出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.2100334
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资金
- National Institute of Allergy and Infectious Diseases, National Institutes of Health R01 Grant [AI083456, T32AI106704]
- Ohio State University (OSU) College of Medicine Roessler Research scholarship [CA016058, UL1TR002733]
- OSU Division of Transplant Surgery
- OSU College of Medicine
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.
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.
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