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Alloreactive memory CD4 T cells promote transplant rejection by engaging DCs to induce innate inflammation and CD8 T cell priming.
Saha, Irene; Chawla, Amanpreet Singh; Oliveira, Ana Paula B N; Elfers, Eileen E; Warrick, Kathrynne; Meibers, Hannah E; Jain, Viral G; Hagan, Thomas; Katz, Jonathan D; Pasare, Chandrashekhar.
Affiliation
  • Saha I; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
  • Chawla AS; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
  • Oliveira APBN; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
  • Elfers EE; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
  • Warrick K; Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
  • Meibers HE; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
  • Jain VG; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
  • Hagan T; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45220.
  • Katz JD; Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
  • Pasare C; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
Proc Natl Acad Sci U S A ; 121(34): e2401658121, 2024 Aug 20.
Article in En | MEDLINE | ID: mdl-39136987
ABSTRACT
Alloreactive memory T cells have been implicated as central drivers of transplant rejection. Perplexingly, innate cytokines, such as IL-6, IL-1ß, and IL-12, are also associated with rejection of organ transplants. However, the pathways of innate immune activation in allogeneic transplantation are unclear. While the role of microbial and cell death products has been previously described, we identified alloreactive memory CD4 T cells as the primary triggers of innate inflammation. Memory CD4 T cells engaged MHC II-mismatched dendritic cells (DCs), leading to the production of innate inflammatory cytokines. This innate inflammation was independent of several pattern recognition receptors and was primarily driven by TNF superfamily ligands expressed by alloreactive memory CD4 T cells. Blocking of CD40L and TNFα resulted in dampened inflammation, and mice genetically deficient in these molecules exhibited prolonged survival of cardiac allografts. Furthermore, myeloid cell and CD8 T cell infiltration into cardiac transplants was compromised in both CD40L- and TNFα-deficient recipients. Strikingly, we found that priming of naive alloreactive CD8 T cells was dependent on licensing of DCs by memory CD4 T cells. This study unravels the key mechanisms by which alloreactive memory CD4 T cells contribute to destructive pathology and transplant rejection.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Dendritic Cells / CD4-Positive T-Lymphocytes / Heart Transplantation / CD8-Positive T-Lymphocytes / Graft Rejection / Immunity, Innate / Inflammation Limits: Animals Language: En Journal: Proc Natl Acad Sci U S A Year: 2024 Document type: Article Country of publication: Estados Unidos

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Dendritic Cells / CD4-Positive T-Lymphocytes / Heart Transplantation / CD8-Positive T-Lymphocytes / Graft Rejection / Immunity, Innate / Inflammation Limits: Animals Language: En Journal: Proc Natl Acad Sci U S A Year: 2024 Document type: Article Country of publication: Estados Unidos