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NK cell-derived IFN-gamma differentially regulates innate resistance and neutrophil response in T cell-deficient hosts infected with Mycobacterium tuberculosis

  1. Author:
    Feng, C. G.
    Kaviratne, M.
    Rothfuchs, A. G.
    Cheever, A.
    Hieny, S.
    Young, H. A.
    Wynn, T. A.
    Sher, A.
  2. Author Address

    NIAID, Parasit Dis Lab, Immunobiol Sect, NIH, Bethesda, MD 20892 USA. NIAID, Parasit Dis Lab, Immunopathogenesis, NIH, Bethesda, MD 20892 USA. Biomed Res Inst, Rockville, MD 20852 USA. NCI, Canc Res Ctr, Expt Immunol Lab, Frederick, MD 21701 USA.;Feng, CG, NIAID, Parasit Dis Lab, Immunobiol Sect, NIH, Room 6148,Bldg 50,50 South Dr, Bethesda, MD 20892 USA.;cfeng@niaid.nih.gov
    1. Year: 2006
    2. Date: Nov
  1. Journal: Journal of Immunology
    1. 177
    2. 10
    3. Pages: 7086-7093
  2. Type of Article: Article
  3. ISSN: 0022-1767
  1. Abstract:

    Although it is known that IFN-gamma-secreting T cells are critical for control of Mycobacterium tuberculosis infection, the contribution of IFN-gamma produced by NK cells to host resistance to the pathogen is less well understood. By using T cell-deficient RAG(-/-) mice, we showed that M. tuberculosis stimulates NK cell-dependent IFN-gamma production in naive splenic cultures and in lungs of infected animals. More importantly, common cytokine receptor gamma-chain(-/-)RAG(-/-) animals deficient in NK cells, p40(-/-)RAG(-/-), or anti-IFN-gamma mAb-treated RAG(-/-) mice displayed significantly increased susceptibility to M. tuberculosis infection compared with untreated NK-sufficient RAG(-/-) controls. Studies comparing IL-12 p40- and p35-deficient RAG(-/-) mice indicated that IL-12 plays a more critical role in the induction of IFN-gamma-mediated antimycobacterial effector functions than IL-23 or other p40-containing IL-12 family members. The increased susceptibility of IL-12-deficient or anti-IFN-gamma mAb-treated RAG(-/-) mice was associated not only with elevated bacterial loads, but also with the development of granulocyte-enriched foci in lungs. This tissue response correlated with increased expression of the granulocyte chemotactic chemokines KC and MIP-2 in NK as well as other leukocyte populations. Interestingly, depletion of granulocytes further increased bacterial burdens and exacerbated pulmonary pathology in these animals, revealing a compensatory function for neutrophils in the absence of IFN-gamma. The above observations indicate that NK cell-derived IFN-gamma differentially regulates T-independent resistance and granulocyte function in M. tuberculosis infection and suggest that this response could serve as an important barrier in AIDS patients or other individuals with compromised CD4(+) T cell function.

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External Sources

  1. WOS: 000242009700060

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