期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：23
页码：7225-7230
DOI：10.1073/pnas.1508224112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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. CD4+ regulatory T (Treg) cells expressing CD25 and the transcription factor forkhead box P3 (FOXP3) are indispensable for immunological self-tolerance and homeostasis. FOXP3+CD25+CD4+ T cells in humans, however, are heterogeneous in function and differentiation status, including suppressive or nonsuppressive cells as well as resting or activated Treg cells. We have searched for cell surface markers specific for suppression-competent Treg cells by using a panel of currently available monoclonal antibodies reactive with human T cells. We found that CD15s (sialyl Lewis x) was highly specific for activated, terminally differentiated, and most suppressive FOXP3high effector Treg (eTreg) cells and able to differentiate them in various clinical settings from nonsuppressive FOXP3+ T cells secreting inflammatory cytokines. For example, CD15s+FOXP3+ eTreg cells were increased in sarcoidosis, whereas it was nonsuppressive CD15s-FOXP3+ T cells that were expanded in lupus flares. FOXP3+ cells induced from conventional CD4+ T cells by T-cell receptor stimulation hardly expressed CD15s. CD15s+CD4+ T-cell depletion was sufficient to evoke and enhance in vitro immune responses against tumor or viral antigens. Collectively, we have identified CD15s as a biomarker instrumental in both phenotypic and functional analysis of FOXP3+CD4+ T-cell subpopulations in health and disease. It allows specific targeting of eTreg cells, rather than whole FOXP3+CD4+ T cells, in controlling immune responses.
