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The human memory T cell compartment changes across tissues of the female reproductive tract

Abstract

Memory CD4 T cells in tissues fulfill numerous functions that are critical for local immune homeostasis and protection against pathogens. Previous studies have highlighted the phenotypic and functional heterogeneity of circulating and tissue-resident memory CD4 T cells across different human tissues such as skin, lung, liver, and colon. Comparatively little is known in regard to memory CD4 T cells across tissues of the female reproductive tract (FRT). We examined CD4 T cells in donor-matched vaginal, ecto- and endocervical tissues, which differ in mucosal structure and exposure to external environmental stimuli. We hypothesized that this could be reflected by tissue-specific differences in the memory CD4 T cell compartment. We found differences in CD4 subset distribution across these tissues. Specifically, CD69+CD103+ CD4 T cells were significantly more abundant in vaginal than cervical tissues. In contrast, the transcriptional profiles of CD4 subsets were fairly conserved across FRT tissues. CD69+CD103+ CD4 T cells showed a TH17 bias independent of tissue niche. Our data suggest that FRT tissues affect T cell subset distribution but have limited effects on the transcriptome of each subset. We discuss the implications for barrier immunity in the FRT.

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Fig. 1: Distinct CD4 to CD8 T cell ratios in FRT tissues.
Fig. 2: CD69+CD103+ cells are enriched in the vaginal tissue and express high levels of PD-1 and CCR5.
Fig. 3: CD69+CD103+ CD4 T cells sorted from vaginal tissue have a unique transcriptional profile.
Fig. 4: CD69+CD103+ CD4 TRM cells in VT are enriched for a TH17 gene signature.
Fig. 5: IL-17A in the VT is primarily produced by CD69+CD103+ CD4 TRM.
Fig. 6: CD69+CD103+ CD4 TRM TH17 gene enrichment is conserved across adjacent mucosal tissues.
Fig. 7: Tissue memory CD4 T cell subsets in adjacent mucosal sites have largely shared transcriptional profiles.

Data availability

RNAseq data available as GEO number GSE163260.

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Acknowledgements

We thank Veronica Davé for her input on statistical analysis and members of the Lund and Prlic labs for critical discussions. This work was supported by NIH grants DP2 DE023321 (M.P.), T32AI07140 (A.S.W.D.), R01 AI141435 and AI131914 (J.M.L.), and R01 DA040386 (F.H.). A.S.W.D. was a Doug and Maggie Walker Fellow.

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A.S.W.D., F.H., J.M.L., and M.P. conceived of the study. A.S.W.D., L.P., S.M.H., G.M.L., A.C.K., M.F.F., and F.H. initiated the study design and helped with implementation. A.S.W.D. and S.C.V. analyzed flow cytometry data, V.V. and R.G. provided statistical expertise and RNAseq data analysis. S.C.V., J.M.L., and M.P. wrote the initial draft of the manuscript, all authors contributed to the final manuscript.

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Correspondence to Jennifer M. Lund or Martin Prlic.

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Woodward Davis, A.S., Vick, S.C., Pattacini, L. et al. The human memory T cell compartment changes across tissues of the female reproductive tract. Mucosal Immunol (2021). https://doi.org/10.1038/s41385-021-00406-6

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