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

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 , negatively regulate activation-induced proliferation of human T cells. We found that expression progressively increased from naïve (T) to central memory (T) to effector memory (T) cells, with a notable upregulation following stimulation. Overexpression of leads to a reduction in T cell proliferation while knockdown promotes proliferation of T and T cells. Furthermore, we demonstrated that HOPX binds to promoters and exerts repressive effects on the expression of and , two positive regulators known to promote T cell proliferation. Importantly, our findings suggest aging is associated with increased expression, and that knockdown of enhances the proliferation of CD8 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.