Keratinocyte-Mediated Activation of the Cytokine TGF-β Maintains Skin Recirculating Memory CD8+ T Cells

Toshiro Hirai; Yukari Zenke; Yi Yang; Laurent Bartholin; Lalit K. Beura; David Masopust; Daniel H. Kaplan

doi:10.1016/j.immuni.2019.03.002

Keratinocyte-Mediated Activation of the Cytokine TGF-β Maintains Skin Recirculating Memory CD8⁺ T Cells

Toshiro Hirai, Yukari Zenke, Yi Yang, Laurent Bartholin, Lalit K. Beura, David Masopust, Daniel H. Kaplan

Research output: Contribution to journal › Article › peer-review

51 Scopus citations

Abstract

Regulated activation of the cytokine TGF-β by integrins α_vβ₆ and α_vβ₈ expressed on keratinocytes is required for residence of epidermal-resident memory T cells, but whether skin-derived signals also affect recirculating memory cells in the skin remains unclear. Here, we show that after resolution of skin vaccinia virus (VV)infection, antigen-specific circulating memory CD8⁺ T cells migrated into skin. In mice lacking α_vβ₆ and α_vβ₈ integrins (Itgb6^−/−Itgb8^fl/fl-K14-cre), the absence of epidermal-activated TGF-β resulted in a gradual loss of E- or P-selectin-binding central and peripheral memory populations, which were rescued when skin entry was inhibited. Skin recirculating memory cells were required for optimal host defense against skin VV infection. These data demonstrate that skin migration can persist after resolution of local skin infection and that the cytokine environment within this nonlymphoid tissue shapes the differentiation state and persistence of the central and peripheral memory-T-cell pool.

Original language	English (US)
Pages (from-to)	1249-1261.e5
Journal	Immunity
Volume	50
Issue number	5
DOIs	https://doi.org/10.1016/j.immuni.2019.03.002
State	Published - May 21 2019

Bibliographical note

Funding Information:
We thank the members of the Kaplan laboratory 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. This work benefitted from a SPECIAL BD LSRFortessa funded by NIH 1S10OD011925-01. T.H. was supported by JSPS Overseas Research Fellowships and D.H.K. by NIH R01AR060744. T.H. and D.H.K. designed and interpreted experiments; T.H. Y.Z. and Y.Y. performed experiments; L.K.B. and D.M. provided technical and conceptual assistance; L.B. contributed a critical reagent. T.H. and D.H.K. wrote the manuscript, and all authors edited it. The authors declare no competing interests.

Funding Information:
We thank the members of the Kaplan laboratory 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. This work benefitted from a SPECIAL BD LSRFortessa funded by NIH 1S10OD011925-01 . T.H. was supported by JSPS Overseas Research Fellowships and D.H.K. by NIH R01AR060744 .

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

CD8 T cell memory
keratinocytes
skin
transforming growth factor beta
αβ
αβ

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1016/j.immuni.2019.03.002

Find It

Find It at U of M Libraries

Cite this

@article{c18de8fb65d44844b7549376d7ed6ffb,

title = "Keratinocyte-Mediated Activation of the Cytokine TGF-β Maintains Skin Recirculating Memory CD8+ T Cells",

abstract = "Regulated activation of the cytokine TGF-β by integrins αvβ6 and αvβ8 expressed on keratinocytes is required for residence of epidermal-resident memory T cells, but whether skin-derived signals also affect recirculating memory cells in the skin remains unclear. Here, we show that after resolution of skin vaccinia virus (VV)infection, antigen-specific circulating memory CD8+ T cells migrated into skin. In mice lacking αvβ6 and αvβ8 integrins (Itgb6−/−Itgb8fl/fl-K14-cre), the absence of epidermal-activated TGF-β resulted in a gradual loss of E- or P-selectin-binding central and peripheral memory populations, which were rescued when skin entry was inhibited. Skin recirculating memory cells were required for optimal host defense against skin VV infection. These data demonstrate that skin migration can persist after resolution of local skin infection and that the cytokine environment within this nonlymphoid tissue shapes the differentiation state and persistence of the central and peripheral memory-T-cell pool.",

keywords = "CD8 T cell memory, keratinocytes, skin, transforming growth factor beta, αβ, αβ",

author = "Toshiro Hirai and Yukari Zenke and Yi Yang and Laurent Bartholin and Beura, {Lalit K.} and David Masopust and Kaplan, {Daniel H.}",

note = "Funding Information: We thank the members of the Kaplan laboratory 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. This work benefitted from a SPECIAL BD LSRFortessa funded by NIH 1S10OD011925-01. T.H. was supported by JSPS Overseas Research Fellowships and D.H.K. by NIH R01AR060744. T.H. and D.H.K. designed and interpreted experiments; T.H. Y.Z. and Y.Y. performed experiments; L.K.B. and D.M. provided technical and conceptual assistance; L.B. contributed a critical reagent. T.H. and D.H.K. wrote the manuscript, and all authors edited it. The authors declare no competing interests. Funding Information: We thank the members of the Kaplan laboratory 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. This work benefitted from a SPECIAL BD LSRFortessa funded by NIH 1S10OD011925-01 . T.H. was supported by JSPS Overseas Research Fellowships and D.H.K. by NIH R01AR060744 . Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = may,

day = "21",

doi = "10.1016/j.immuni.2019.03.002",

language = "English (US)",

volume = "50",

pages = "1249--1261.e5",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

number = "5",

}

TY - JOUR

T1 - Keratinocyte-Mediated Activation of the Cytokine TGF-β Maintains Skin Recirculating Memory CD8+ T Cells

AU - Hirai, Toshiro

AU - Zenke, Yukari

AU - Yang, Yi

AU - Bartholin, Laurent

AU - Beura, Lalit K.

AU - Masopust, David

AU - Kaplan, Daniel H.

N1 - Funding Information: We thank the members of the Kaplan laboratory 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. This work benefitted from a SPECIAL BD LSRFortessa funded by NIH 1S10OD011925-01. T.H. was supported by JSPS Overseas Research Fellowships and D.H.K. by NIH R01AR060744. T.H. and D.H.K. designed and interpreted experiments; T.H. Y.Z. and Y.Y. performed experiments; L.K.B. and D.M. provided technical and conceptual assistance; L.B. contributed a critical reagent. T.H. and D.H.K. wrote the manuscript, and all authors edited it. The authors declare no competing interests. Funding Information: We thank the members of the Kaplan laboratory 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. This work benefitted from a SPECIAL BD LSRFortessa funded by NIH 1S10OD011925-01 . T.H. was supported by JSPS Overseas Research Fellowships and D.H.K. by NIH R01AR060744 . Publisher Copyright: © 2019 Elsevier Inc.

PY - 2019/5/21

Y1 - 2019/5/21

N2 - Regulated activation of the cytokine TGF-β by integrins αvβ6 and αvβ8 expressed on keratinocytes is required for residence of epidermal-resident memory T cells, but whether skin-derived signals also affect recirculating memory cells in the skin remains unclear. Here, we show that after resolution of skin vaccinia virus (VV)infection, antigen-specific circulating memory CD8+ T cells migrated into skin. In mice lacking αvβ6 and αvβ8 integrins (Itgb6−/−Itgb8fl/fl-K14-cre), the absence of epidermal-activated TGF-β resulted in a gradual loss of E- or P-selectin-binding central and peripheral memory populations, which were rescued when skin entry was inhibited. Skin recirculating memory cells were required for optimal host defense against skin VV infection. These data demonstrate that skin migration can persist after resolution of local skin infection and that the cytokine environment within this nonlymphoid tissue shapes the differentiation state and persistence of the central and peripheral memory-T-cell pool.

AB - Regulated activation of the cytokine TGF-β by integrins αvβ6 and αvβ8 expressed on keratinocytes is required for residence of epidermal-resident memory T cells, but whether skin-derived signals also affect recirculating memory cells in the skin remains unclear. Here, we show that after resolution of skin vaccinia virus (VV)infection, antigen-specific circulating memory CD8+ T cells migrated into skin. In mice lacking αvβ6 and αvβ8 integrins (Itgb6−/−Itgb8fl/fl-K14-cre), the absence of epidermal-activated TGF-β resulted in a gradual loss of E- or P-selectin-binding central and peripheral memory populations, which were rescued when skin entry was inhibited. Skin recirculating memory cells were required for optimal host defense against skin VV infection. These data demonstrate that skin migration can persist after resolution of local skin infection and that the cytokine environment within this nonlymphoid tissue shapes the differentiation state and persistence of the central and peripheral memory-T-cell pool.

KW - CD8 T cell memory

KW - keratinocytes

KW - skin

KW - transforming growth factor beta

KW - αβ

UR - http://www.scopus.com/inward/record.url?scp=85065713887&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065713887&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2019.03.002

DO - 10.1016/j.immuni.2019.03.002

M3 - Article

C2 - 30952606

AN - SCOPUS:85065713887

SN - 1074-7613

VL - 50

SP - 1249-1261.e5

JO - Immunity

JF - Immunity

IS - 5

ER -