Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis

Eszter Lázár-Molnár, Bing Chen, Kari A. Sweeney, Emilie J. Wang, Weijun Liu, Juan Lin, Steven A. Porcelli, Steven C. Almo, Stanley G. Nathenson, William R. Jacobs

Research output: Contribution to journalArticle

149 Citations (Scopus)

Abstract

The programmed death-1 (PD-1) costimulatory receptor inhibits T and B cell responses and plays a crucial role in peripheral tolerance. PD-1 has recently been shown to inhibit T cell responses during chronic viral infections such as HIV. In this study, we examined the role of PD-1 in infection with Mycobacterium tuberculosis, a common co-infection with HIV. PD-1-deficient mice showed dramatically reduced survival compared with wild-type mice. The lungs of the PD-1-/- mice showed uncontrolled bacterial proliferation and focal necrotic areas with predominantly neutrophilic infiltrates, but a lower number of infiltrating T and B cells. Proinflammatory cytokines, such as TNF-α, IL-1, and especially IL-6 and IL-17 were significantly increased in the lung and sera of infected PD-1-/- mice, consistent with an aberrant inflammation. Microarray analysis of the lungs infected with M. tuberculosis showed dramatic differences between PD-1-/- and control mice. Using high-stringency analysis criteria (changes of twofold or greater), 367 transcripts of genes were differentially expressed between infected PD-1 -/- and wild-type mice, resulting in profoundly altered inflammatory responses with implications for both innate and adaptive immunity. Overall, our studies show that the PD-1 pathway is required to control excessive inflammatory responses after M. tuberculosis infection in the lungs.

Original languageEnglish (US)
Pages (from-to)13402-13407
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number30
DOIs
StatePublished - Jul 27 2010

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Tuberculosis
Mycobacterium tuberculosis
Lung
T-Lymphocytes
B-Lymphocytes
HIV
Peripheral Tolerance
Mycobacterium Infections
Interleukin-17
Adaptive Immunity
Virus Diseases
Microarray Analysis
Coinfection
Interleukin-1
Innate Immunity
Interleukin-6
Cytokines
Inflammation
Infection
Serum

Keywords

  • Co-inhibitory
  • Costimulatory
  • Infection

ASJC Scopus subject areas

  • General
  • Medicine(all)

Cite this

Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis. / Lázár-Molnár, Eszter; Chen, Bing; Sweeney, Kari A.; Wang, Emilie J.; Liu, Weijun; Lin, Juan; Porcelli, Steven A.; Almo, Steven C.; Nathenson, Stanley G.; Jacobs, William R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 30, 27.07.2010, p. 13402-13407.

Research output: Contribution to journalArticle

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