McDaniel, Chawla, and Jain et al. investigated mechanisms of inflammatory cytokine pathology common to T cell-mediated autoimmune diseases and cancer immunotherapies. Effector memory CD4+ T cells (TEM) were shown to interact with myeloid cells, such as DCs and macrophages, and to stimulate CD40- and TNFR-dependent inflammation, which was independent of pattern recognition receptor activation. Blocking TNF and CD40 signaling in several models of T cell-driven inflammation rescued animals from cytokine storm and toxicity, suggesting TEM-driven innate myeloid cell activation is a key trigger of immunopathology.
Contributed by Katherine Turner
ABSTRACT: Cytokine storm and sterile inflammation are common features of T cell-mediated autoimmune diseases and T cell-targeted cancer immunotherapies. Although blocking individual cytokines can mitigate some pathology, the upstream mechanisms governing overabundant innate inflammatory cytokine production remain unknown. Here, we have identified a critical signaling node that is engaged by effector memory T cells (T(EM)) to mobilize a broad proinflammatory program in the innate immune system. Cognate interactions between T(EM) and myeloid cells led to induction of an inflammatory transcriptional profile that was reminiscent, yet entirely independent, of classical pattern recognition receptor (PRR) activation. This PRR-independent "de novo" inflammation was driven by preexisting T(EM) engagement of both CD40 and tumor necrosis factor receptor (TNFR) on myeloid cells. Cytokine toxicity and autoimmune pathology could be completely rescued by ablating these pathways genetically or pharmacologically in multiple models of T cell-driven inflammation, indicating that T(EM) instruction of the innate immune system is a primary driver of associated immunopathology. Thus, we have identified a previously unknown trigger of cytokine storm and autoimmune pathology that is amenable to therapeutic interventions.
Author Info: (1) Immunology Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Division of Immunobiology, Cincinnati Children's Hospital Medical Center, C
Author Info: (1) Immunology Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. (2) Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. (3) Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. (4) Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA. (5) Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. (6) Immunology Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (7) Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA. (8) Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH 45220, USA. (9) Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH 45220, USA. Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. (10) Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH 45220, USA.
