TNFα and IFNγ but not perforin are critical for CD8 T cell-mediated protection against pulmonary Yersinia pestis infection.
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.
Trudeau Institute, Saranac Lake, New York, United States of America.
Frank M
FM
Szaba
Trudeau Institute, Saranac Lake, New York, United States of America.
Lawrence W
LW
Kummer
Trudeau Institute, Saranac Lake, New York, United States of America.
Debra K
DK
Duso
Trudeau Institute, Saranac Lake, New York, United States of America.
Ekaterina P
EP
Koroleva
Trudeau Institute, Saranac Lake, New York, United States of America.
Alexei V
AV
Tumanov
Trudeau Institute, Saranac Lake, New York, United States of America.
Andrea M
AM
Cooper
Center for Infectious Diseases and Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, United States of America.
James B
JB
Bliska
Trudeau Institute, Saranac Lake, New York, United States of America.
Stephen T
ST
Smiley
Trudeau Institute, Saranac Lake, New York, United States of America.
Jr-Shiuan
JS
Lin
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D007111:Immunity, Cellular / Q000235:genetics*; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010930:Plague / Q000150:complications / Q000235:genetics / Q000276:immunology*; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology*; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*; D015010:Yersinia pestis / Q000276:immunology*
D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; C483886:perforin, mouse; D007371:Interferon-gamma