TNFα and IFNγ but Not Perforin Are Critical for CD8 T Cell-Mediated Protection against Pulmonary Yersinia pestis Infection

PLoS Pathogens

James B. Bliska¹  Andrea M. Cooper²  Jr-Shiuan Lin²  Stephen T. Smiley²  Alexei V. Tumanov²  Debra K. Duso²  Frank M. Szaba²  Lawrence W. Kummer²  Ekaterina P. Koroleva² 

[1] Center for Infectious Diseases and Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, United States of America;Trudeau Institute, Saranac Lake, New York, United States of America

关键词: T cells;    Cytotoxic T cells;    Yersinia pestis;    Mouse models;    Cytokines;    Yersinia pseudotuberculosis;    Lethality (bacteriology);    Bone marrow cells;   

DOI  :  10.1371/journal.ppat.1004142

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Septic pneumonias resulting from bacterial infections of the lung are a leading cause of human death worldwide. Little is known about the capacity of CD8 T cell-mediated immunity to combat these infections and the types of effector functions that may be most effective. Pneumonic plague is an acutely lethal septic pneumonia caused by the Gram-negative bacterium Yersinia pestis. We recently identified a dominant and protective Y. pestis antigen, YopE69–77, recognized by CD8 T cells in C57BL/6 mice. Here, we use gene-deficient mice, Ab-mediated depletion, cell transfers, and bone marrow chimeric mice to investigate the effector functions of YopE69–77-specific CD8 T cells and their relative contributions during pulmonary Y. pestis infection. We demonstrate that YopE69–77-specific CD8 T cells exhibit perforin-dependent cytotoxicity in vivo; however, perforin is dispensable for YopE69–77-mediated protection. In contrast, YopE69–77-mediated protection is severely impaired when production of TNFα and IFNγ by CD8 T cells is simultaneously ablated. Interestingly, TNFα is absolutely required at the time of challenge infection and can be provided by either T cells or non-T cells, whereas IFNγ provided by T cells prior to challenge appears to facilitate the differentiation of optimally protective CD8 T cells. We conclude that cytokine production, not cytotoxicity, is essential for CD8 T cell-mediated control of pulmonary Y. pestis infection and we suggest that assays detecting Ag-specific TNFα production in addition to antibody titers may be useful correlates of vaccine efficacy against plague and other acutely lethal septic bacterial pneumonias.

【 授权许可】

CC BY