Cutting Edge: Expression of TNFR2 Defines a Maximally Suppressive Subset of Mouse CD4 super(+)CD25 super(+)FoxP3 super(+) T Regulatory Cells: Applicability to Tumor-Infiltrating T Regulatory Cells

TNFR2 is predominantly expressed by a subset of human and mouse CD4 super(+)CD25 super(+)FoxP3 super(+) T regulatory cells (Tregs). In this study, we characterized the phenotype and function of TNFR2 super(+) Tregs in peripheral lymphoid tissues of normal and tumor-bearing C57BL/6 mice. We found that TNFR2 was expressed on 30-40% of the Tregs of the peripheral activated/memory subset that were most highly suppressive. In contrast, TNFR2 super(-) Tregs exhibited the phenotype of naive cells and only had minimal suppressive activity. Although not typically considered to be Tregs, CD4 super(+)CD25 super(-)TNFR2 super(+) cells nevertheless possessed moderate suppressive activity. Strikingly, the suppressive activity of TNFR2 super(+) Tregs was considerably more potent than that of reportedly highly suppressive CD103 super(+) Tregs. In the Lewis lung carcinoma model, more highly suppressive TNFR2 super(+) Tregs accumulated intratumorally than in the periphery. Thus, TNFR2 identifies a unique subset of mouse Tregs with an activated/memory phenotype and maximal suppressive activity that may account for tumor-infiltrating lymphocyte-mediated immune evasion by tumors.