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Aberrant Tissue Localization of Fungus-Specific CD4⁺ T Cells in IL-10-Deficient Mice¹

Amariliz Rivera^2,*, Nichole Collins^*, Matthias T. Stephan^3,, Lauren Lipuma^*, Ingrid Leiner^* and Eric G. Pamer^*,

^* Immunology Program, Center for Cell Engineering, Molecular Pharmacology and Chemistry Program, Infectious Diseases Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

Aspergillus fumigatus, a common environmental fungus, can cause lethal invasive infections in immunocompromised hosts. In immunocompetent individuals, however, inhaled A. fumigatus spores prime CD4⁺ T cells and activate immune responses that prevent invasive infection. Calibration of inflammatory responses to levels that prevent fungal invasion without inducing collateral tissue damage is essential for host survival, but the underlying regulatory mechanisms remain undefined. Although IL-10 is a validated regulatory cytokine that suppresses immune responses, and IL-10 deficiency or blockade generally enhances immune responses, we find that A. fumigatus-specific T cell frequencies are markedly reduced in airways of IL-10-deficient mice. T cell priming, proliferation, and survival were unaffected by IL-10 deficiency and did not account for decreased frequencies of A. fumigatus-specific T cells in the airways of IL-10-deficient mice. Instead, IL-10 deficiency results in redistribution of A. fumigatus-specific T cells from infected lungs to the gut, a process that is reversed by antibiotic-mediated depletion of intestinal microbes. Our studies demonstrate that disregulated immune responses in the gut can result in dramatic redistribution of pathogen-specific T cells within the host.

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 This work was supported by the Sandler Program in Asthma Research and by National Institutes of Health Grants 1K01CA117914 (to A.R.), P01CA59350 (to M.T.S.), and AI067359 (to E.G.P.).

² Address correspondence and reprint requests to Dr. Amariliz Rivera, Immunology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 9, New York, NY 10065. E-mail address: riverama{at}mskcc.org

³ Current address: Koch Institute for Integrative Cancer Research, Immunobioengineering Laboratory, Massachusetts Institute of Technology, Room 8-425, 77 Massachusetts Avenue, Cambridge, MA 02139.

⁴ Abbreviations used in this paper: IA, invasive aspergillosis; MLN, mediastinal lymph node; IBD, inflammatory bowel disease; MNV, metronidazole, neomycin, and vancomycin; WT, wild type; tg, transgenic.

⁵ The online version of this article contains supplemental material.