NK cell-derived IFN-gamma differentially regulates innate resistance and neutrophil response in T cell-deficient hosts infected with Mycobacterium tuberculosis.
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.
Feng
Carl G
CG
Immunobiology Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-8003, USA. cfeng@niaid.nih.gov
Kaviratne
Mallika
M
Rothfuchs
Antonio Gigliotti
AG
Cheever
Allen
A
Hieny
Sara
S
Young
Howard A
HA
Wynn
Thomas A
TA
Sher
Alan
A
D000818:Animals; D006098:Granulocytes / Q000276:immunology / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology*; D018664:Interleukin-12 / Q000502:physiology; D053759:Interleukin-23 / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008231:Lymphopenia / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000401:mortality / Q000473:pathology
D018398:Homeodomain Proteins; D053759:Interleukin-23; C064658:RAG-1 protein; D018664:Interleukin-12; D007371:Interferon-gamma