MyD88 Shapes Vaccine Immunity by Extrinsically Regulating Survival of CD4+ T Cells during the Contraction Phase

PLoS Pathogens

Chiung Yu Hung¹  Clifford A. Lowell²  Meenal Sinha²  Anthony L. DeFranco³  Linda M. Lee³  Marulasiddappa Suresh⁴  Bruce S. Klein⁵  Mengyi Li⁵  Kevin Galles⁵  Huafeng Wang⁵  Vanessa LeBert⁵  Darin L. Wiesner⁵  Tassanee Lerksuthirat⁵  Marcel Wüthrich⁶ 

[1] Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio, San Antonio, Texas, United States of America;Department of Laboratory Medicine, University of California at San Francisco, San Francisco, California, United States of America;Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, California, United States of America;Department of Pathobiological Sciences, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America;Departments of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America;Internal Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America

关键词: T cells;    Vaccines;    Cytokines;    Immune receptor signaling;    Vaccination;    immunization;    Spleen;    T helper cells;    Cell differentiation;   

DOI  :  10.1371/journal.ppat.1005787

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Soaring rates of systemic fungal infections worldwide underscore the need for vaccine prevention. An understanding of the elements that promote vaccine immunity is essential. We previously reported that Th17 cells are required for vaccine immunity to the systemic dimorphic fungi of North America, and that Card9 and MyD88 signaling are required for the development of protective Th17 cells. Herein, we investigated where, when and how MyD88 regulates T cell development. We uncovered a novel mechanism in which MyD88 extrinsically regulates the survival of activated T cells during the contraction phase and in the absence of inflammation, but is dispensable for the expansion and differentiation of the cells. The poor survival of activated T cells in Myd88-/- mice is linked to increased caspase3-mediated apoptosis, but not to Fas- or Bim-dependent apoptotic pathways, nor to reduced expression of the anti-apoptotic molecules Bcl-2 or Bcl-xL. Moreover, TLR3, 7, and/or 9, but not TLR2 or 4, also were required extrinsically for MyD88-dependent Th17 cell responses and vaccine immunity. Similar MyD88 requirements governed the survival of virus primed T cells. Our data identify unappreciated new requirements for eliciting adaptive immunity and have implications for designing vaccines.

【 授权许可】

CC BY