CD4+CD25high regulatory cells in human peripheral blood.
Thymectomy in mice on neonatal day 3 leads to the development of multiorgan autoimmune disease due to loss of a CD(+)CD25(+) T cell regulatory population in their peripheral lymphoid tissues. Here, we report the identification of a CD4(+) population of regulatory T cells in the circulation of humans expressing high levels of CD25 that exhibit in vitro characteristics identical with those of the CD4(+)CD25(+) regulatory cells isolated in mice. With TCR cross-linking, CD4(+)CD25(high) cells did not proliferate but instead totally inhibited proliferation and cytokine secretion by activated CD4(+)CD25(-) responder T cells in a contact-dependent manner. The CD4(+)CD25(high) regulatory T cells expressed high levels of CD45RO but not CD45RA, akin to the expression of CD45RB(low) on murine CD4(+)CD25(+) regulatory cells. Increasing the strength of signal by providing either costimulation with CD28 cross-linking or the addition of IL-2 to a maximal anti-CD3 stimulus resulted in a modest induction of proliferation and the loss of observable suppression in cocultures of CD4(+)CD25(high) regulatory cells and CD4(+)CD25(-) responder cells. Whereas higher ratios of CD4(+)CD25(high) T cells are required to suppress proliferation if the PD-L1 receptor is blocked, regulatory cell function is shown to persist in the absence of the PD-1/PD-L1 or CTLA-4/B7 pathway. Thus, regulatory CD4 T cells expressing high levels of the IL-2 receptor are present in humans, providing the opportunity to determine whether alterations of these populations of T cells are involved in the induction of human autoimmune disorders.
Baecher-Allan
C
C
Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115. callan@rics.bwh.harvard.edu
Brown
J A
JA
Freeman
G J
GJ
Hafler
D A
DA
D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; D015704:CD4 Antigens / Q000096:biosynthesis* / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D018920:Coculture Techniques; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006801:Humans; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000235:genetics; D007700:Kinetics; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008562:Membrane Glycoproteins; D010455:Peptides / Q000502:physiology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis* / Q000097:blood; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; C423236:CD274 protein, human; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D006684:HLA-DR Antigens; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D010455:Peptides; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D000069594:Abatacept; D017493:Leukocyte Common Antigens