Human CD4+CD25+ Regulatory T Cells Share Equally Complex and Comparable Repertoires with CD4+CD25− Counterparts

Abstract

CD4⁺CD25⁺ T cells are critical mediators of peripheral immune tolerance. However, many developmental and functional characteristics of these cells are unknown, and knowledge of human regulatory T cells is particularly limited. To better understand how human CD4⁺CD25⁺ T cells develop and function, we examined the diversity of CD4⁺CD25⁺ and CD4⁺CD25⁻ T cell repertoires in both thymus and peripheral blood. Levels of T receptor excision circles (TREC) were comparable in purified CD4⁺CD25⁺ and CD4⁺CD25⁻ thymic populations, but were significantly higher than those in samples derived from peripheral blood, consistent with murine studies demonstrating thymic development of CD4⁺CD25⁺ regulatory T cells. Surprisingly, CD4⁺CD25⁻ T cells isolated from peripheral blood had greater TREC quantities than their CD4⁺CD25⁺ counterparts, supporting the possibility of extrathymic expansion as well. CD4⁺CD25⁺ and CD4⁺CD25⁻ T cells from a given individual showed overlapping profiles with respect to diversity by Vβ staining and spectratyping. Interestingly, CD4⁺CD25⁺ T cells have lower quantities of CD3 than CD4⁺CD25⁻ T cells. Collectively, these data suggest that human CD4⁺CD25⁺ T cells recognize a similar array of Ags as CD4⁺CD25⁻ T cells. However, reduced levels of TCR on regulatory T cells suggest different requirements for activation and may contribute to how the immune system regulates whether a particular response is suppressed or augmented.