Key Points
In vivo development of alloprimed CD8+ CTLs requires iNKT or CD4+ T cell help.
iNKTs promote the in vivo development of alloprimed CXCR3+CCR4+CD8+ T cells.
CXCR3+CCR4+CD8+ T cells are a multipotent, highly cytotoxic CD8+ T cell subset.
Visual Abstract
Abstract
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 Jα18 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+CCR4−CD8+ T cells by a higher proportion of cells expressing TNF-α and IFN-γ. 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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Footnotes
This work was supported by National Institute of Allergy and Infectious Diseases, National Institutes of Health R01 Grant AI083456 (to G.L.B.) and T32AI106704 (to J.H.), The Ohio State University (OSU) College of Medicine Roessler Research scholarship (to B.A.R.), CA016058, UL1TR002733, the OSU Division of Transplant Surgery, and the OSU College of Medicine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The online version of this article contains supplemental material.
Abbreviations used in this article
- AT
- adoptive transfer
- DC
- dendritic cell
- DN
- double-negative
- FasL
- Fas ligand
- α-GalCer
- α-galactosylceramide
- hA1AT
- human α-1 antitrypsin
- iNKT
- invariant NKT
- KO
- knockout
- LMNC
- liver mononuclear cell
- MST
- median survival time
- Treg
- regulatory T cell
- WT
- wild-type
- Received April 8, 2021.
- Accepted October 13, 2021.
- Copyright © 2021 by The American Association of Immunologists, Inc.
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