TGF-b/TIF1g signaling restrains CD8+ T cell expansion while preserving cytotoxic competence

Abstract

Transforming growth factor b exerts complex and often opposing effects on CD8+ T cell biology, yet the molecular mechanisms that distinguish these functions remain poorly understood. Here, we identify TIF1g (TRIM33) as a critical signal threshold regulator that couples TGF b signaling to CD8+ T cell activation and cytotoxic function. In the presence of TGF b, TIF1g deficient CD8+ T cells bypass canonical suppressive signals and acquire a transcriptional program characterized by enhanced activation and proliferation. Despite this hyperactivated state, TIF1g deficient cells fail to acquire full effector function, exhibiting markedly reduced Granzyme B and Perforin expression under TGF b signaling. We confirmed this functional uncoupling in vivo using a secondary Listeria monocytogenes challenge model, in which TIF1g deficient CD8+ T cells underwent robust expansion yet failed to efficiently control bacterial infection because of impaired cytotoxic activity. In a lymphopenic homeostatic proliferation model, TIF1g deficiency disrupted cellular quiescence, leading to excessive proliferation and spontaneous effector differentiation. Consistent with these findings, loss of TIF1g accelerated B16 melanoma growth and was associated with reduced Perforin expression in tumor-infiltrating CD8+ T cells. Together, these findings identify TIF1g as a key regulator of TGF b mediated CD8+ T cell responses, uncoupling activation from cytotoxic differentiation and revealing a mechanism by which TGF b independently regulates proliferative and effector programs.