Invariant NKT Cells Promote the Development of Highly Cytotoxic Multipotent CXCR3+CCR4+CD8+ T Cells That Mediate Rapid Hepatocyte Allograft Rejection
| العنوان: | Invariant NKT Cells Promote the Development of Highly Cytotoxic Multipotent CXCR3+CCR4+CD8+ T Cells That Mediate Rapid Hepatocyte Allograft Rejection |
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| المؤلفون: | Jing Han, Madison M Hart, Ginny L. Bumgardner, Robert T. Warren, Chelsea M Peterson, Bryce A Ringwald, Sachi R Chaudhari, Mahmoud Abdel-Rasoul, Jason M. Zimmerer |
| المصدر: | J Immunol |
| بيانات النشر: | The American Association of Immunologists, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Graft Rejection, Adoptive cell transfer, T cell, Immunology, CD8-Positive T-Lymphocytes, Article, Mice, Immune system, medicine, Animals, Immunology and Allergy, Cytotoxic T cell, Mice, Knockout, biology, Chemistry, Allografts, Natural killer T cell, Liver Transplantation, Mice, Inbred C57BL, medicine.anatomical_structure, Perforin, Granzyme, Hepatocytes, Cancer research, biology.protein, Natural Killer T-Cells, CD8 |
| الوصف: | 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. |
| تدمد: | 1550-6606 0022-1767 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::72bd6691be0e085cab8786d555bd82bd https://doi.org/10.4049/jimmunol.2100334 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....72bd6691be0e085cab8786d555bd82bd |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15506606 00221767 |
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