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Immunologic Homeostasis during Infection: Coexistence of Strong Pulmonary Cell-Mediated Immunity to Secondary Cryptococcus neoformans Infection While the Primary Infection Still Persists at Low Levels in the Lungs¹

Dennis M. Lindell^*,, Megan N. Ballinger^*,, Roderick A. McDonald^*, Galen B. Toews^* and Gary B. Huffnagle^2,*,,

^* Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Immunology Graduate Program, and Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109

Maintenance of immunity to persistent pathogens is poorly understood. In this study, we used a murine model of persistent pulmonary fungal infection to study the ongoing cell-mediated immune response. CBA/J mice with low-level persistent Cryptococcus neoformans infection had CD4⁺ T cells of effector memory phenotype present in their lungs. Although unable to eliminate the primary infection to sterility, these mice displayed hallmarks of immunologic memory in response to rechallenge with C. neoformans: 1) the secondary cryptococcal challenge was controlled much more rapidly, 2) the inflammatory response developed and resolved more rapidly, 3) CD4⁺ T and CD8⁺ T cell responses were higher in magnitude, and 4) effector cytokine production by T cells was greatly enhanced. Depletion of CD4⁺ T cells at the time of secondary challenge adversely affected clearance of C. neoformans from the lungs. These results demonstrate that persistent low-level infection with C. neoformans does not impair the cell-mediated response to the fungus. Although they are relatively free of overt disease, these mice can respond with a rapid secondary immune response if the burden of C. neoformans increases. These data support the concept that immunologically healthy individuals can maintain low numbers of cryptococci that can become a nidus for re-activation disease during immunodeficient states such as AIDS.

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 National Institutes of Health Grants R01-HL065912 (to G.B.H.), R01-AI059201 (to G.B.H.), R01-HL051082 (to G.B.T.), R01-AI049448 (to T.A.M.), T32-AI07413 (to D.M.L.), and Department of Veterans Affairs Merit Grant (to G.B.T.).

² Address correspondence and reprint requests to Dr. Gary B. Huffnagle, Pulmonary and Critical Care Medicine, 6301 MSRB III, University of Michigan Medical Center, Ann Arbor, MI 48109-0642. E-mail address: ghuff{at}umich.edu

³ Abbreviations used in this paper: HKC, heat-killed C. neoformans; MFI, mean fluorescence intensity; MedFI, median fluorescence intensity.

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