Alloreactive memory CD4 T cells promote transplant rejection by engaging DCs to induce innate inflammation and CD8 T cell priming

• 成果类型: Article
• 署名作者: 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
• 署名单位: Cincinnati Children's Hospital Medical Center; University System of Ohio; University of Cincinnati; Cincinnati Children's Hospital Medical Center; University System of Ohio; University of Cincinnati; Cincinnati Children's Hospital Medical Center; Cincinnati Children's Hospital Medical Center; University System of Ohio; University of Cincinnati; University System of Ohio; University of Cincinnati; University of Alabama System; University of Alabama Birmingham; University System of Ohio; University of Cincinnati
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14157
• DOI: 10.1073/pnas.2401658121
• 发表日期: 2024-08-20
• 关键词: versus-host-disease; conventional dendritic cells; allograft-rejection; regulatory protein; danger signal; in-vivo; donor; antigen; RECOGNITION; RISK

摘要

Alloreactive memory T cells have been implicated as central drivers of transplant rejection. Perplexingly, innate cytokines, such as IL- 6, IL- 1f3, 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 TNF alpha 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 TNF alpha- 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.