Cytotoxic CD4⁺ T cells and their implication in oral diseases and systemic diseases with oral manifestations

T cells are derived from multipotent stem cells in the bone marrow and migrate to the thymus, where they differentiate into two main subpopulations: CD4⁺ T cells and CD8⁺ T cells. It is usually believed that CD4⁺ T cells mainly play a supplementary function in immune processes such as antibody production, antigen-specific CD8⁺ T cell activation, and immune regulation; whereas CD8⁺ T cells are able to kill the target cells through cell killing mechanism, and play an important role in the immune defense against intracellular pathogens and tumor immunity. A unique cytotoxic subpopulation of CD4⁺ T cells, designated CD4⁺ cytotoxic T lymphocytes (CD4⁺ CTLs), has emerged as a significant focus of research in recent years. This review focuses on biological properties and mechanisms of CD4⁺ CTLs, as well as the research progress of CD4⁺ CTLs in oral diseases and systemic diseases with oral manifestations, including Sjögren's syndrome, IgG4-related disease, HIV infection, and inflammatory bowel disease, with the aim of elucidating the contributions of CD4⁺ CTLs to disease pathogenesis and uncovering novel therapeutic targets for these conditions.