SignificanceCD4+ regulatory T (Treg) cells expressing CD25 and the transcription factor forkhead box P3 (FOXP3) play indispensable roles for immunological self-tolerance and homeostasis. Because human FOXP3+CD25+CD4+ T cells are heterogeneous in function and differentiation status, their analysis and manipulation for treating immunological diseases remains a challenge. Here we show that CD15s (sialyl Lewis x) is specifically expressed by activated, terminally differentiated, and most suppressive FOXP3high Treg cells, allowing their separation from nonsuppressive FOXP3+CD4+ T cells secreting inflammatory cytokines. Removal of CD15s+CD4+ T cells from human blood is indeed sufficient to enhance in vitro antitumor and antiviral antigen responses. CD15s is therefore useful for phenotypic as well as functional analysis of human Treg subpopulations and for targeting them to control immune responses.

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