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Altered CD4⁺ T Cell Phenotype and Function Determine the Susceptibility to Mucosal Candidiasis in Transgenic Mice Expressing HIV-1¹

Daniel Lewandowski^*, Miriam Marquis^*, Francine Aumont^*, Annie-Claude Lussier-Morin^*, Marianne Raymond^*, Serge Sénéchal^*, Zaher Hanna^,,, Paul Jolicoeur^*,, and Louis de Repentigny^2,*,¶

^* Department of Microbiology and Immunology, Department of Medicine, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada; Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada; Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada; and ^¶ Sainte-Justine Hospital, Montreal, Quebec, Canada

The impairments of protective mucosal immunity which cause susceptibility to oropharyngeal candidiasis (OPC) in HIV infection remain undefined. This study used a model of OPC in CD4C/HIV MutA transgenic (Tg) mice expressing Rev, Env, and Nef of HIV-1 to investigate the role of transgene expressing dendritic cells (DCs) and CD4⁺ T cells in maintenance of chronic oral carriage of Candida albicans. DCs were depleted in the Tg mice and had an immature phenotype, with low expression of MHC class II and IL-12. CD4⁺ T cells were quantitatively reduced in the oral mucosa, cervical lymph nodes (CLNs) and peripheral blood of the Tg mice, and displayed a polarization toward a nonprotective Th2 response. Proliferation of CLN CD4⁺ T cells from infected Tg mice in response to C. albicans Ag in vitro was abrogated and the cells failed to acquire an effector phenotype. Coculture of C. albicans-pulsed DCs with CD4⁺ T cells in vitro showed that Tg expression in either or both of these cell populations sharply reduced the proliferation of CD4⁺ T cells and their production of IL-2. Finally, transfer of naive non-Tg CD4⁺ T cells into these Tg mice restored proliferation to C. albicans Ag and sharply reduced oral burdens of C. albicans. Overall, these results indicate that defective CD4⁺ T cells primarily determine the susceptibility to chronic carriage of C. albicans in these Tg mice.