CD4+ cytotoxic T cells: context-dependent effectors in health and disease

Abstract Cytotoxic CD4 + T cells (CD4 + CTLs) have been identified as a specialized effector population characterized by potent cytotoxic machinery, including granzymes, perforin, and the Fas/FasL pathway, that enables the direct killing of MHC-II-expressing target cells. In addition to their classical helper function, CD4 + CTLs exhibit remarkable functional plasticity, which is dynamically influenced by a multilayered regulatory network integrating intrinsic transcriptional programs, extrinsic immune checkpoints, and tissue-specific microenvironmental signals. This context-dependent behavior makes CD4 + CTLs a double-edged sword in human health and disease. CD4 + CTLs are involved in protective immunity against viruses, tumors, and in eliminating senescent cells .However, they can also contribute to immunopathology in conditions such as autoimmune diseases, fibrotic disorders, atherosclerosis, and allograft rejection. Although advances in single-cell technologies have revealed the heterogeneity and TCR repertoire features, applying this knowledge to develop safe and effective therapies continues to be a significant challenge. Major obstacles include inherent plasticity, phenotypic instability, risk of off-target effects, and discrepancies between preclinical models and human diseases. This review highlights recent advances in understanding the development, regulation, and effector functions of CD4 + CTLs, while also addressing the limitations and challenges in targeting them therapeutically. Ultimately, this perspective positions CD4 + CTLs as both targets for intervention and tools for immunotherapy.