Dataset Information

Developmentally distinct CD4⁺ T_reg lineages shape the CD8⁺ T cell response to acute Listeria infection.

ABSTRACT: SignificanceThe CD4⁺ T_reg response following acute Listeria infection is heterogeneous and deploys two distinct modes of suppression coinciding with initial pathogen exposure and resolution of infection. This bimodal suppression of CD8⁺ T cells during priming and contraction is mediated by separate T_reg lineages. These findings make a significant contribution to our understanding of the functional plasticity inherent within T_reg_s, which allows these cells to serve as a sensitive and dynamic cellular rheostat for the immune system to prevent autoimmune pathology in the face of inflammation attendant to acute infection, enable expansion of the pathogen-specific response needed to control the infection, and reestablish immune homeostasis after the threat has been contained.

SUBMITTER: Dolina JS

PROVIDER: S-EPMC8915796 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

Developmentally distinct CD4+ Treg lineages shape the CD8+ T cell response to acute Listeria infection.

Dolina Joseph S JS Lee Joey J Moore Eugene L EL Hope Jennifer L JL Gracias Donald T DT Matsutani Takaji T Chawla Ashu A Greenbaum Jason A JA Linden Joel J Schoenberger Stephen P SP

Proceedings of the National Academy of Sciences of the United States of America 20220303 10

SignificanceThe CD4+ Treg response following acute Listeria infection is heterogeneous and deploys two distinct modes of suppression coinciding with initial pathogen exposure and resolution of infection. This bimodal suppression of CD8+ T cells during priming and contraction is mediated by separate Treg lineages. These findings make a significant contribution to our understanding of the functional plasticity inherent within Tregs ...[more]

PMID: 35239442

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Project description:Sepsis is a systemic immune response to infection that is responsible for ~35% of in-hospital deaths and over 24 billion dollars in annual treatment costs. Strategic targeting of non-redundant negative immune checkpoint protein pathways can cater therapeutics to the individual septic patient and improve prognosis. B7-CD28 superfamily member V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an ideal candidate for strategic targeting in sepsis. We hypothesized that immune checkpoint regulator, VISTA, controls T-regulatory cells (Treg), in response to septic challenge, thus playing a protective role/reducing septic morbidity/mortality. Further, we investigated if changes in morbidity/mortality are due to a Treg-mediated effect during the acute response to septic challenge. To test this, we used the cecal ligation and puncture model as a proxy for polymicrobial sepsis and assessed the phenotype of CD4+ Tregs in VISTA-gene deficient (VISTA-/-) and wild-type mice. We also measured changes in survival, soluble indices of tissue injury, and circulating cytokines in the VISTA-/- and wild-type mice. We found that in wild-type mice, CD4+ Tregs exhibit a significant upregulation of VISTA which correlates with higher Treg abundance in the spleen and small intestine following septic insult. However, VISTA-/- mice have reduced Treg abundance in these compartments met with a higher expression of Foxp3, CTLA4, and CD25 compared to wild-type mice. VISTA-/- mice also have a significant survival deficit, higher levels of soluble indicators of liver injury (i.e., ALT, AST, bilirubin), and increased circulating proinflammatory cytokines (i.e., IL-6, IL-10, TNFα, IL-17F, IL-23, and MCP-1) following septic challenge. To elucidate the role of Tregs in VISTA-/- sepsis mortality, we adoptively transferred VISTA-expressing Tregs into VISTA-/- mice. This adoptive transfer rescued VISTA-/- survival to wild-type levels. Taken together, we propose a protective Treg-mediated role for VISTA by which inflammation-induced tissue injury is suppressed and improves survival in early-stage murine sepsis. Thus, enhancing VISTA expression or adoptively transferring VISTA+ Tregs in early-stage sepsis may provide a novel therapeutic approach to ameliorate inflammation-induced death.

Dataset Information

Developmentally distinct CD4⁺ T_reg lineages shape the CD8⁺ T cell response to acute Listeria infection.

Publications

Developmentally distinct CD4<sup>+</sup> T<sub>reg</sub> lineages shape the CD8<sup>+</sup> T cell response to acute <i>Listeria</i> infection.

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