AUTHOR=Canaria D. Alejandro , Rodriguez J. Alejandra , Wang Luopin , Yeo Franklin J. , Yan Bingyu , Wang Mengbo , Campbell Charlotte , Kazemian Majid , Olson Matthew R. 

TITLE=Tox induces T cell IL-10 production in a BATF-dependent manner

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1275423

DOI=10.3389/fimmu.2023.1275423

ISSN=1664-3224

ABSTRACT=<p>Tox is a member of the high mobility group (HMG)-Box transcription factors and plays important roles in thymic T cell development. Outside of the thymus, however, Tox is also highly expressed by CD8 and CD4 T cells in various states of activation and in settings of cancer and autoimmune disease. In CD4 T cells, Tox has been primarily studied in T follicular helper (TFH) cells where it, along with Tox2, promotes TFH differentiation by regulating key TFH-associated genes and suppressing CD4 cytotoxic T cell differentiation. However, the role of Tox in other T helper (Th) cell subtypes is less clear. Here, we show that Tox is expressed in several physiologically-activated Th subtypes and its ectopic expression enhances the <italic>in vitro</italic> differentiation of Th2 and T regulatory (Treg) cells. Tox overexpression in unpolarized Th cells also induced the expression of several genes involved in cell activation (<italic>Pdcd1</italic>), cellular trafficking (<italic>Ccl3, Ccl4, Xcl1</italic>) and suppressing inflammation (<italic>Il10</italic>) across multiple Th subtypes. We found that Tox binds the regulatory regions of these genes along with the transcription factors BATF, IRF4, and JunB and that Tox-induced expression of IL-10, but not PD-1, is BATF-dependent. Based on these data, we propose a model where Tox regulates Th cell chemotactic genes involved in facilitating dendritic cell-T cell interactions and aids in the resolution or prevention of inflammation through the production of IL-10.</p>