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Type 1 Treg cells promote the generation of CD8+ tissue-resident memory T cells

Abstract

Tissue-resident memory T (TRM) cells, functionally distinct from circulating memory T cells, have a critical role in protective immunity in tissues, are more efficacious when elicited after vaccination and yield more effective antitumor immunity, yet the signals that direct development of TRM cells are incompletely understood. Here we show that type 1 regulatory T (Treg) cells, which express the transcription factor T-bet, promote the generation of CD8+ TRM cells. The absence of T-bet-expressing type 1 Treg cells reduces the presence of TRM cells in multiple tissues and increases pathogen burden upon infectious challenge. Using infection models, we show that type 1 Treg cells are specifically recruited to local inflammatory sites via the chemokine receptor CXCR3. Close proximity with effector CD8+ T cells and Treg cell expression of integrin-β8 endows the bioavailability of transforming growth factor-β in the microenvironment, thereby promoting the generation of CD8+ TRM cells.

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Fig. 1: Foxp3-dependent Tbx21 excision results in reduced number of type 1 Treg cells.
Fig. 2: Foxp3-dependent Tbx21 excision results in alterations in CD8+ T cell populations.
Fig. 3: Reduced development of TRM cells in absence of type 1 Treg cells.
Fig. 4: Reduced TRM cell development results in increased susceptibility to infection.
Fig. 5: Recruitment of type 1 Treg cells determines TRM cell differentiation.
Fig. 6: Type 1 Treg cells promote TRM cell development via TGF-β availability.

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Acknowledgements

We acknowledge the excellent contributions from the iMM flow cytometry, rodent, histology and microscopy facilities. The project leading to these results has received funding from the European Union H2020 ERA project (no. 667824, EXCELLtoINNOV), Fundo iMM-Laço and ‘la caixa’ Foundation (ID 100010434) under agreement LCF/PR/HR19/52160005 for work in the Veldhoen laboratory, with additional funding from the Fundação para a Ciência e a Tecnologia to P.F.-C. (SFRH/BD/131605/2017), to L.B. (PD/BD/138847/2018) and to A.B. (SFRH/BD/138900/2018). In addition, the work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) SFB1366 (project no. 394046768-SFB 1366; C02) and by SPP 1937 (CE 140/2-1) to A.C and SFB1292 (TP13) and TR156 (TPB02) to H.C.P. A.L. was supported by Ligue Nationale Contre le Cancer. Other grants supporting this study: Foncer Contre le Cancer (JCM) and EL-2016 LNCC Labelisation Ligue Nationale Contre Cancer. TL-tetramer was obtained through the National Institutes of Health Tetramer Core Facility.

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C.F., L.B., S.K., B.B., P.F.-C. and M.B. performed the experiments and provided assistance. A.B. performed bioinformatics analysis. A.S. and A.C. provided CXCR3-deficient animals. N.K. and H.C.P. provided EBI3-deficient animals and performed analysis. A.L. and J.C.M. provided Foxp3Cre Itgb8f/f and Foxp3Cre Tgfb1f/f animals and performed analysis. C.F. and M.V. conceived and directed the experiments and wrote the manuscript with input from all authors.

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Correspondence to Cristina Ferreira or Marc Veldhoen.

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Ferreira, C., Barros, L., Baptista, M. et al. Type 1 Treg cells promote the generation of CD8+ tissue-resident memory T cells. Nat Immunol 21, 766–776 (2020). https://doi.org/10.1038/s41590-020-0674-9

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