CD8+ T Cell Activation Leads to Constitutive Formation of Liver Tissue-Resident Memory T Cells that Seed a Large and Flexible Niche in the Liver

Lauren E Holz,Julia E Prier,David Freestone,Thiago M Steiner,Kieran English,Darryl N Johnson,Vanessa Mollard,Anton Cozijnsen,Gayle M Davey,Dale I Godfrey,Katsuyuki Yui,Laura K Mackay,Mireille H Lahoud,Irina Caminschi,Geoffrey I Mcfadden,Patrick Bertolino,Daniel Fernandez-Ruiz,William R Heath

doi:10.1016/j.celrep.2018.08.094

Abstract

Liver tissue-resident memory T (Trm) cells migrate throughout the sinusoids and are capable of protecting against malaria sporozoite challenge. To gain an understanding of liver Trm cell development, we examined various conditions for their formation. Although liver Trm cells were found in naive mice, their presence was dictated by antigen specificity and required IL-15. Liver Trm cells also formed after adoptive transfer of invitro-activated but not naive CD8+ Tcells, indicating that activation was essential but that antigen presentation within the liver was not obligatory. These Trm cells patrolled the liver sinusoids with a half-life of 36days and occupied a large niche that could be added to sequentially without effect on subsequent Trm cell cohorts. Together, our findings indicate that liver Trm cells form as a normal consequence of CD8+ Tcell activation during essentially any infection but that inflammatory and antigenic signals preferentially tailor their development.

Highlights

Tissue-resident memory T cells are a recently described population of cells that are crucial for defense against pathogens at the site of infection (Schenkel and Masopust, 2014)
Protection mediated by Trm cells has been associated with the production of cytokines, such as interferon-g (IFN-g) and tumor necrosis factor a (TNF-a), as well as markers of cytotoxicity, such as granzyme B and CD107a (Fernandez-Ruiz et al, 2016), indicating that these cells are poised to respond to immediate threats
To begin to address this question, we tested for the presence of Trm cells in the livers of naive T cell receptor (TCR) transgenic mice that had not been exposed to their specific antigen

Summary

Introduction

Tissue-resident memory T cells are a recently described population of cells that are crucial for defense against pathogens at the site of infection (Schenkel and Masopust, 2014) As their name suggests, these cells do not recirculate like their effector memory T (Tem) and central memory T (Tcm) cell counterparts but, instead, remain localized within specific tissues (Jiang et al, 2012; Klonowski et al, 2004). Trm cells found in all tissues typically express the early activation marker CD69 and often CD103, but these markers do not precisely define Trm cells (Steinert et al, 2015) Regardless of their surface profiles, Trm cells found in all tissues express a core gene signature associated with residency, including the expression of Hobit, Ctla, Cdh, Cdh, Cd244, and Xcl (Mackay et al, 2013). Protection mediated by Trm cells has been associated with the production of cytokines, such as interferon-g (IFN-g) and tumor necrosis factor a (TNF-a), as well as markers of cytotoxicity, such as granzyme B and CD107a (Fernandez-Ruiz et al, 2016), indicating that these cells are poised to respond to immediate threats

Methods

Results

Discussion

Conclusion