Although tissue-resident memory T cells (TRM cells) are critical in fighting infection, their fate after local pathogen re-encounter is unknown. Here we found that skin TRM cells engaged virus-infected cells, proliferated in situ in response to local antigen encounter and did not migrate out of the epidermis, where they exclusively reside. As a consequence, secondary TRM cells formed from pre-existing TRM cells, as well as from precursors recruited from the circulation. Newly recruited antigen-specific or bystander TRM cells were generated in the skin without displacement of the pre-existing TRM cell pool. Thus, pre-existing skin TRM cell populations are not displaced after subsequent infections, which enables multiple TRM cell specificities to be stably maintained within the tissue.

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We thank C. Jones, G. Davey, M. Damtsis and N. Zamudio for technical assistance. S.L.P. was supported by the University of Melbourne (Elizabeth and Vernon Puzey Postgraduate Scholarship). T.G. was supported by a fellowship from the Sylvia and Charles Viertel Charitable Foundation. This work was supported by the National Health and Medical Research Council of Australia (to S.N.M. and L.K.M.) and the Australian Research Council (to S.N.M.).

Author information

Author notes

  1. Simone L. Park and Ali Zaid contributed equally to this work.

  2. Scott N. Mueller and Laura K. Mackay jointly supervised this work.


  1. Department of Microbiology and Immunology, The University of Melbourne and The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia

    • Simone L. Park
    • , Ali Zaid
    • , Jyh Liang Hor
    • , Susan N. Christo
    • , Julia E. Prier
    • , Brooke Davies
    • , Yannick O. Alexandre
    • , Julia L. Gregory
    • , Thomas Gebhardt
    • , Francis R. Carbone
    • , William R. Heath
    • , Scott N. Mueller
    •  & Laura K. Mackay
  2. John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia

    • Tiffany A. Russell
    •  & David C. Tscharke
  3. The Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Melbourne, Melbourne, VIC, Australia

    • William R. Heath
    • , Scott N. Mueller
    •  & Laura K. Mackay


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S.L.P., A.Z., J.L.H., S.N.C., J.E.P., B.D., Y.O.A., J.L.G., S.N.M. and L.K.M. performed experiments and analyzed data. T.A.R. and D.C.T. provided reagents. S.L.P., A.Z., T.G., F.R.C., W.R.H., S.N.M. and L.K.M. contributed to experimental design. S.L.P., S.N.M. and L.K.M. prepared the manuscript. S.N.M. and L.K.M. led the research program.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Scott N. Mueller or Laura K. Mackay.

Integrated supplementary information

Supplementary information


  1. Supplementary Video 1

    Transcutaneous delivery of soluble peptide. IV-2PM of EGFP+gBT-I TRM cells in DNFB-treated skin from 3 h after transcutaneous application of OVA or gB peptide

  2. Supplementary Video 2

    gBT-I recall with HSV–mCherry. IV-2PM of EGFP+ gBT-I TRM cells in DNFB-treated skin of mice infected with HSV–mCherry above the DNFB patch 3.5 d previously

  3. Supplementary Video 3

    OT-I recall with HSV–mCherry. IV-2PM of EGFP+ OT-I TRM cells in DNFB-treated skin of mice infected with HSV–mCherry above the DNFB patch 3.5 d previously

  4. Supplementary Video 4

    gBT-I Thy1.1 TRM recall with HSV–mCherry after Thy1.1 antibody depletion. IV-2PM of EGFP+Thy1.1+ gBT-I TRM cells in DNFB-treated skin of Thy1.1 antibody-treated mice infected with HSV–mCherry 4 d previously