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NK Cell-Derived IFN- Differentially Regulates Innate Resistance and Neutrophil Response in T Cell-Deficient Hosts Infected with Mycobacterium tuberculosis

Carl G. Feng^1,*, Mallika Kaviratne, Antonio Gigliotti Rothfuchs^*, Allen Cheever, Sara Hieny^*, Howard A. Young, Thomas A. Wynn and Alan Sher^*

^* Immunobiology Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892; Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892; Biomedical Research Institute, Rockville, MD 20852; and Laboratory of Experimental Immunology, National Cancer Institute, Center for Cancer Research, Frederick, MD 21702

Although it is known that IFN--secreting T cells are critical for control of Mycobacterium tuberculosis infection, the contribution of IFN- 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- production in naive splenic cultures and in lungs of infected animals. More importantly, common cytokine receptor -chain^–/–RAG^–/– animals deficient in NK cells, p40^–/–RAG^–/–, or anti-IFN- 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--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- 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-. The above observations indicate that NK cell-derived IFN- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Carl G. Feng, Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Room 6148, Building 50, 50 South Drive, Bethesda, MD 20892-8003. E-mail address: cfeng{at}niaid.nih.gov

² Abbreviations used in this paper: NOS2, NO synthase type 2; _c, common cytokine receptor -chain; MOI, multiplicity of infection; F, forward; R, reverse; p.i., postinfection; WT, wild type.

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