Regulatory T cells (Tregs) mediate immune homeostasis, yet also facilitate nuanced immune responses during infection, balancing pathogen control while limiting host inflammation. Recent studies have identified Treg populations in non-lymphoid tissues that are phenotypically distinct from Tregs in lymphoid tissues (LT), including performance of location-dependent roles. Mucosal tissues serve as critical barriers to microbes while performing unique physiologic functions, so we sought to identify distinct phenotypical and functional aspects of mucosal Tregs in the female reproductive tract. In healthy human and mouse vaginal mucosa, we found that Tregs are highly activated compared to blood or LT Tregs. To determine if this phenotype reflects acute activation or a general signature of vaginal tract (VT)-residency, we infected mice with HSV-2 to discover that VT Tregs express granzyme-B (GzmB) and acquire a VT Treg signature distinct from baseline. To determine the mechanisms that drive GzmB expression, we performed ex vivo assays to reveal that a combination of type-I interferons and interleukin-2 is sufficient for GzmB expression. Together, we highlight that VT Tregs are activated at steady state and become further activated in response to infection; thus, they may exert robust control of local immune responses, which could have implications for mucosal vaccine design.
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The sequencing data from this publication have been deposited in the NCBI’s Gene Expression Omnibus and are accessible through the series accession number GEO: GSE189375. All scripts used for data processing and figure generation are available at GitHub: https://github.com/Brianna-Traxinger/scRNAseq_vaginalTreg_HSV-2.
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We thank the members of the Lund and Prlic labs for their helpful input and discussions and the study participants. Select figure graphics were created with Biorender.com.
This work was funded by the National Institute of Allergy and Infectious Disease of the US National Institutes of Health (R01 AI141435 and AI131914 to J.M.L.). J.R.E. and S.C.V. were funded by the Diseases of Public Health Importance Training Grant (T32 AI007509) and B.R.T. was funded by the Viral Pathogenesis Training Grant (T32 AI083203).
The authors declare no competing interests.
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Traxinger, B., Vick, S.C., Woodward-Davis, A. et al. Mucosal viral infection induces a regulatory T cell activation phenotype distinct from tissue residency in mouse and human tissues. Mucosal Immunol 15, 1012–1027 (2022). https://doi.org/10.1038/s41385-022-00542-7