Viperin deficiency in CD4⁺ T cells enhances protective immunity against Mycobacterium tuberculosis infection

Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health threat. CD4⁺ T cells are indispensable for protective immunity against Mtb infection. This study defines the T-cell-intrinsic role of Viperin (encoded by Rsad2) during Mtb infection. We utilized T cell-specific Viperin knockout (Rsad2cko) mice and adoptive transfer models into Rag1-/- hosts to assess outcomes following aerosol Mtb infection. We found that Viperin deficiency in CD4⁺ T cells significantly reduced bacterial burden and pathology in Mtb-infected lungs. This enhanced protection was associated with an increased frequency and activation of Mtb-specific CD4⁺ T cells. Viperin-deficient CD4⁺ T cells exhibited enhanced early activation, proliferation, and a bias towards differentiating into short-lived effector memory (Tem) over central memory (Tcm) cells. Furthermore, these cells showed a pronounced skewing towards a Th1 phenotype, with robust IFN-γ production, both in vivo and under Th1-polarizing conditions in vitro. Viperin-deficient CD4⁺ T cells displayed reduced apoptosis and increased activation of the PI3K-Akt-mTOR and PKC-θ-NF-κB pro-survival pathways upon T cell receptor (TCR) stimulation, accompanied by transcriptional downregulation of the pro-apoptotic mediator Bbc3 (PUMA) and the proliferation brake Gadd45a in vivo. Collectively, our study reveals that Viperin intrinsically dampens CD4⁺ T cell function by restraining Th1 differentiation, proliferation, and survival, thereby identifying Viperin as a potential immunotherapeutic target for enhancing T cell-mediated defense against TB. These findings also highlight a context-dependent duality of Viperin, which is protective in viral infection but detrimental in Mtb infection, underscoring its role as a homeostatic regulator of T cell immunity.