Competition for Active TGFβ Cytokine Allows for Selective Retention of Antigen-Specific Tissue- Resident Memory T Cells in the Epidermal Niche

Toshiro Hirai, Yi Yang, Yukari Zenke, Haiyue Li, Virendra K. Chaudhri, Jacinto S. De La Cruz Diaz, Paul Yifan Zhou, Breanna Anh Thu Nguyen, Laurent Bartholin, Creg J. Workman, David W. Griggs, Dario A.A. Vignali, Harinder Singh, David Masopust, Daniel H Kaplan

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Following antigen-driven expansion in lymph node, transforming growth factor-β (TGFβ) is required for differentiation of skin-recruited CD8+ T cell effectors into epidermal resident memory T (Trm) cells and their epidermal persistence. We found that the source of TGFβ -supporting Trm cells was autocrine. In addition, antigen-specific Trm cells that encountered cognate antigen in the skin, and bystander Trm cells that did not, both displayed long-term persistence in the epidermis under steady-state conditions. However, when the active-TGFβ was limited or when new T cell clones were recruited into the epidermis, antigen-specific Trm cells were more efficiently retained than bystander Trm cells. Genetically enforced TGFβR signaling allowed bystander Trm cells to persist in the epidermis as efficiently as antigen-specific Trm cells in both contexts. Thus, competition between T cells for active TGFβ represents an unappreciated selective pressure that promotes the accumulation and persistence of antigen-specific Trm cells in the epidermal niche.

Original languageEnglish (US)
Pages (from-to)84-98.e5
JournalImmunity
Volume54
Issue number1
DOIs
StatePublished - Jan 12 2021

Bibliographical note

Funding Information:
We thank Kate M. Vignali and Andrea L. Workman for constructing E8I-creER T2 and ROSA26.LSL.hNGFR reporter mice. We thank the members of the Kaplan and Vignali laboratory and members throughout the departments of Dermatology and Immunology for helpful discussions. We also thank the Division of Laboratory Animal Resources of the University of Pittsburgh for excellent animal care. The graphical abstract was created with BioRender.com . This work benefitted from SPECIAL BD LSRFORTESSATM , funded by NIH 1S10OD011925-01 . T.H. was supported by JSPS Overseas Research Fellowships; J.S.D. by NIH T32 AI089443 and AR060744S1 ; D.H.K. by NIH R01AR060744 ; and D.A.A.V. by NIH P01AI108545 .

Funding Information:
We thank Kate M. Vignali and Andrea L. Workman for constructing E8I-creERT2 and ROSA26.LSL.hNGFR reporter mice. We thank the members of the Kaplan and Vignali laboratory and members throughout the departments of Dermatology and Immunology for helpful discussions. We also thank the Division of Laboratory Animal Resources of the University of Pittsburgh for excellent animal care. The graphical abstract was created with BioRender.com. This work benefitted from SPECIAL BDLSRFORTESSATM, funded by NIH 1S10OD011925-01. T.H. was supported by JSPS Overseas Research Fellowships; J.S.D. by NIH T32 AI089443 and AR060744S1; D.H.K. by NIH R01AR060744; and D.A.A.V. by NIH P01AI108545. T.H. and D.H.K. designed and interpreted experiments; T.H. Y.Y. Y.Z. H.L. J.S.D. P.Y.Z. and B.A.N. performed experiments; L.B. C.J.W. and D.A.A.V. contributed a critical reagents; V.K.C. and H.S. conducted the bioinformatics analysis.; D.M. and D.W.G. provided technical and conceptual assistance; T.H. and D.H.K. wrote the manuscript and all authors edited it. D.W.G. is a consultant and equity holder of Indalo Therapeutics, which provided compound CWHM-12. All other authors declare no competing interests.

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

  • TGFβ
  • antigen
  • bystander Trm
  • competition
  • keratinocytes
  • niche
  • resident memory T cells
  • skin
  • αβ
  • αβ

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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