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

CG Feng, M Kaviratne, AG Rothfuchs… - The Journal of …, 2006 - journals.aai.org
CG Feng, M Kaviratne, AG Rothfuchs, A Cheever, S Hieny, HA Young, TA Wynn, A Sher
The Journal of Immunology, 2006journals.aai.org
Although it is known that IFN-γ-secreting T cells are critical for control of Mycobacterium
tuberculosis infection, the contribution of IFN-γ 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-γ production in naive splenic cultures and in
lungs of infected animals. More importantly, common cytokine receptor γ-chain−/− RAG−/−
animals deficient in NK cells, p40−/− RAG−/−, or anti-IFN-γ mAb-treated RAG−/− mice …
Abstract
Although it is known that IFN-γ-secreting T cells are critical for control of Mycobacterium tuberculosis infection, the contribution of IFN-γ 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-γ production in naive splenic cultures and in lungs of infected animals. More importantly, common cytokine receptor γ-chain−/− RAG−/− animals deficient in NK cells, p40−/− RAG−/−, or anti-IFN-γ 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-γ-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-γ 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-γ. The above observations indicate that NK cell-derived IFN-γ 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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