The effector program of human CD8 T cells supports tissue remodeling

#A 83-01 ;  #9094360 ;

J Exp Med. 2024 Feb 5;221(2):e20230488. doi: 10.1084/jem.20230488.

Michael Delacher ^{# 1 2 3 4}, Lisa Schmidleithner ^# 1 2, Malte Simon ^# 1 5 6, Philipp Stüve ^# 1 2, Lieke Sanderink ^1 2, Agnes Hotz-Wagenblatt ⁷, Marina Wuttke ^1 2, Kathrin Schambeck ^1 2, Brigitte Ruhland ^1 2, Veronika Hofmann ^1 2, Sebastian Bittner ^1 2, Uwe Ritter ^1 2, Asmita Pant ^1 2, Sara Salome Helbich ^3 4, Morten Voss ^3 4, Niels A Lemmermann ^4 8 9, Lisa Bessiri-Schake ^3 4, Toszka Bohn ^3 4, Andreas Eigenberger ¹⁰, Ayse Nur Menevse ^1 11, Claudia Gebhard ¹, Nicholas Strieder ¹, Hinrich Abken ^1 12, Michael Rehli ^1 13, Jochen Huehn ^14 15 16, Philipp Beckhove ^1 11 13, Thomas Hehlgans ^1 2, Henrik Junger ¹⁷, Edward K Geissler ¹⁷, Lukas Prantl ¹⁰, Jens M Werner ¹⁷, Christian Schmidl ¹, Benedikt Brors ^{5 18 6 19 20}, Charles D Imbusch ^3 4 6, Markus Feuerer ^1 2

• PMID: 38226976
• PMCID: PMC10791561
• DOI: 10.1084/jem.20230488

Abstract

CD8 T lymphocytes are classically viewed as cytotoxic T cells. Whether human CD8 T cells can, in parallel, induce a tissue regeneration program is poorly understood. Here, antigen-specific assay systems revealed that human CD8 T cells not only mediated cytotoxicity but also promoted tissue remodeling. Activated CD8 T cells could produce the epidermal growth factor receptor (EGFR)-ligand amphiregulin (AREG) and sensitize epithelial cells for enhanced regeneration potential. Blocking the EGFR or the effector cytokines IFN-γ and TNF could inhibit tissue remodeling. This regenerative program enhanced tumor spheroid and stem cell-mediated organoid growth. Using single-cell gene expression analysis, we identified an AREG+, tissue-resident CD8 T cell population in skin and adipose tissue from patients undergoing abdominal wall or abdominoplasty surgery. These tissue-resident CD8 T cells showed a strong TCR clonal relation to blood PD1+TIGIT+ CD8 T cells with tissue remodeling abilities. These findings may help to understand the complex CD8 biology in tumors and could become relevant for the design of therapeutic T cell products.