AUTHOR=Yang Qian , Patrick Michael , Lu Jian , Chen Joseph , Zhang Yongqing , Hemani Humza , Lehrmann Elin , De Supriyo , Weng Nan-ping 

TITLE=Homeodomain-only protein suppresses proliferation and contributes to differentiation- and age-related reduced CD8+ T cell expansion

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1360229

DOI=10.3389/fimmu.2024.1360229

ISSN=1664-3224

ABSTRACT=<p>T cell activation is a tightly controlled process involving both positive and negative regulators. The precise mechanisms governing the negative regulators in T cell proliferation remain incompletely understood. Here, we report that homeodomain-only protein (HOPX), a homeodomain-containing protein, and its most abundant isoform <italic>HOPXb</italic>, negatively regulate activation-induced proliferation of human T cells. We found that <italic>HOPX</italic> expression progressively increased from naïve (T<sub>N</sub>) to central memory (T<sub>CM</sub>) to effector memory (T<sub>EM</sub>) cells, with a notable upregulation following <italic>in vitro</italic> stimulation. Overexpression of <italic>HOPXb</italic> leads to a reduction in T<sub>N</sub> cell proliferation while <italic>HOPX</italic> knockdown promotes proliferation of T<sub>N</sub> and T<sub>EM</sub> cells. Furthermore, we demonstrated that HOPX binds to promoters and exerts repressive effects on the expression of <italic>MYC</italic> and <italic>NR4A1</italic>, two positive regulators known to promote T cell proliferation. Importantly, our findings suggest aging is associated with increased <italic>HOPX</italic> expression, and that knockdown of <italic>HOPX</italic> enhances the proliferation of CD8<sup>+</sup> T cells in older adults. Our findings provide compelling evidence that HOPX serves as a negative regulator of T cell activation and plays a pivotal role in T cell differentiation and in age-related-reduction in T cell proliferation.</p>