MHC class II expression identifies functionally distinct human regulatory T cells.
It has been known for decades that circulating human CD4 cells can express functional MHC class II molecules that induce T cell nonresponsiveness with Ag presentation. Because there is significant expression of MHC class II (MHC-II) determinants (DR) on a subpopulation CD4+ CD25(high) regulatory T cells (Treg), we examined the function of CD4 cells expressing MHC-DR. We demonstrate that MHC-II expression on human CD4+ CD25(high) T cells identifies a functionally distinct population of Treg that induces early contact-dependent suppression that is associated with high Foxp3 expression. In striking contrast, MHC-II- CD4+ CD25(high) Treg induce early IL-4 and IL-10 secretion and a late Foxp3-associated contact-dependent suppression. The DR expressing CD25(high) Treg express higher levels of Foxp3 message and protein, compared with the DR- CD25(high) Treg population. Direct single-cell cloning of CD4+ CD25(high) Treg revealed that, regardless of initial DR expression, ex vivo expression of CD25(high), and not DR, predicted which clones would exhibit contact-dependent suppression, high levels of Foxp3 message, and an increased propensity to become constitutive for DR expression. Thus, the direct ex vivo expression of MHC-II in the context of CD25(high) identifies a mature, functionally distinct regulatory T cell population involved in contact-dependent in vitro suppression.
Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA. callan@rics.bwh.harvard.edu
Clare
C
Baecher-Allan
Elizabeth
E
Wolf
David A
DA
Hafler
D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000145:classification / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics; D015870:Gene Expression; D006684:HLA-DR Antigens / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000145:classification* / Q000276:immunology*
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; C508609:IL10 protein, human; C508598:IL4 protein, human; D015375:Receptors, Interleukin-2; D016753:Interleukin-10; D015847:Interleukin-4