Helios⁺ and Helios^- Treg subpopulations are phenotypically and functionally distinct and express dissimilar TCR repertoires.

The transcription factor Helios is expressed in a large subset of Foxp3⁺ Tregs. We previously proposed that Helios is a marker of thymic derived Treg (tTreg), while Helios^- Treg were induced from Foxp3^- T conventional (Tconv) cells in the periphery (pTreg). To compare the two Treg subpopulations, we generated Helios-GFP reporter mice and crossed them to Foxp3-RFP reporter mice. The Helios⁺ Treg population expressed a more activated phenotype, had a slightly higher suppressive capacity in vitro and expressed a more highly demethylated TSDR but were equivalent in their ability to suppress inflammatory bowel disease in vivo. However, Helios⁺ Treg more effectively inhibited the proliferation of activated, autoreactive splenocytes from scurfy mice. When Helios⁺ and Helios^- Treg were transferred to lymphoreplete mice, both populations maintained comparable Foxp3 expression, but Foxp3 expression was less stable in Helios^- Treg when transferred to lymphopenic mice. Gene expression profiling demonstrated a large number of differentially expressed genes and showed that Helios^- Treg expressed certain genes normally expressed in CD4⁺ Foxp3^- T cells. TCR repertoire analysis indicated very little overlap between Helios⁺ and Helios^- Treg. Thus, Helios⁺ and Helios^- Treg subpopulations are phenotypically and functionally distinct and express dissimilar TCR repertoires.

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