Developmental plasticity allows outside-in immune responses by resident memory T cells


Central memory T (TCM) cells patrol lymph nodes and perform conventional memory responses on restimulation: proliferation, migration and differentiation into diverse T cell subsets while also self-renewing. Resident memory T (TRM) cells are parked within single organs, share properties with terminal effectors and contribute to rapid host protection. We observed that reactivated TRM cells rejoined the circulating pool. Epigenetic analyses revealed that TRM cells align closely with conventional memory T cell populations, bearing little resemblance to recently activated effectors. Fully differentiated TRM cells isolated from small intestine epithelium exhibited the potential to differentiate into TCM cells, effector memory T cells and TRM cells on recall. Ex-TRM cells, former intestinal TRM cells that rejoined the circulating pool, heritably maintained a predilection for homing back to their tissue of origin on subsequent reactivation and a heightened capacity to redifferentiate into TRM cells. Thus, TRM cells can rejoin the circulation but are advantaged to re-form local TRM when called on.

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Fig. 1: Local reactivation of TRM cells precipitates egress to circulation.
Fig. 2: Epigenetic profiling of TRM cells reveals memory state with potential developmental plasticity.
Fig. 3: Transdifferentiation of TRM cells into circulating memory T cell subsets.
Fig. 4: Developmental plasticity and tissue redistribution of TCM and TRM cells.
Fig. 5: Ex-TRM cells remain epigenetically poised for migration and TRM cell redifferentiation.
Fig. 6: Ex-TRM cells are poised to reacquire TRM cell characteristics in response to cytokines.

Data availability

All original data are available from the corresponding author upon request.


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We thank the members of the Masopust laboratory and the University of Minnesota Center for Immunology for helpful discussions. We were funded by a National Institutes of Health grant (no. R01AI084913), the Howard Hughes Medical Institute Scholars program (to D.M.) and an FAPESP-BEPE (2015/00680-7) fellowship (to R.F).

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R.F., L.K.B., C.F.Q., N.J.F.-F., S.W., E.A.T. and H.B.S. performed and analyzed the experiments. H.E.G. and Y.F. performed and analyzed the WGBS. C.C.Z. and M.C.S. conducted the bioinformatics analysis. R.F., L.K.B., C.F.Q., N.J.F.-F., V.V., B.Y. and D.M. designed the experiments and prepared the manuscript. D.M. was responsible for research supervision, coordination and strategy.

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Correspondence to David Masopust.

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Fonseca, R., Beura, L.K., Quarnstrom, C.F. et al. Developmental plasticity allows outside-in immune responses by resident memory T cells. Nat Immunol 21, 412–421 (2020).

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