Specialized subset of CD4+ T cells involved in the regulation of T and B cell activation. Recruited to the TIME by chemokines and cytokines such as CXCL12, produced by tumor cells and other immunosuppressive cells. Can suppress host immune response by direct cell-cell contacts through CTLA-4 and LAG-3 inhibitory signals, and granzyme/perforin expression and production of immunosuppressive metabolites and cytokines e.g. (IL-10 and TGF-β). Can activate TGF-β secretion by tumor cells, a major cancer immune-escape mechanism. (15–17). This evidence concerns the gene PRF1 and neoplasm.