CD4⁺CD25^-FoxP3⁺ T cells: a distinct subset or a heterogeneous population?

In addition to generating effective immunity against infectious agents, the immune system helps to fight against different noninfectious human diseases while maintaining the balance between self and non-self discrimination. The breakdown of tolerance in autoimmune diseases or sustainable tolerance in an abnormal microenvironment such as chronic inflammation may initiate the process of malignancy. Immune system regulation is controlled by a complex, dynamic network of cells and mediators. Understanding the cellular and molecular basis of immune regulation provides better insight into the mechanisms governing the immune pathology of diseases. Among several cellular subsets and mediators with regulatory roles, a subpopulation of CD4⁺ T cells was recently reported to be positive for FoxP3 and negative for CD25, with a suggested range of functional activities in both cancer and autoimmune diseases. This CD4 subset was first reported in 2006 and thought to have a role in the pathogenesis of cancer. However, the spectrum of roles played by this T cell subset is broad, and no consensus has been reached regarding its immunological functions. In this review, we focused on the possible origin of CD4⁺CD25^‒FoxP3⁺ T cells and their function in cancer and autoimmune diseases.