CD4+CD25+ regulatory cells from human peripheral blood express very high levels of CD25 ex vivo.
Selective isolation of only those CD4+ T cells that display the highest levels of CD25 by FACS results in a highly homogeneous regulatory population as defined by functional activity and the expression of multiple surface antigens. Thus greater than 98% of CD4+CD25high cells express CD45RO in the absence of CD45RA expression. Upon TCR stimulation CD4+CD25high cells are both anergic and tolerogenic as they inhibit proliferation and cytokine secretion by activated CD4+CD25- responder T cells in a contact-dependent manner. In contrast, CD4+ cells that express lower levels of CD25 are more heterogeneous in their levels of expression of CD45RO, HLA-DR and CD122, and do not exhibit anergic or suppressive characteristics. Providing either CD28 co-stimulation or IL2 to a maximal anti-CD3 stimulus results in a modest induction of proliferation and the loss of observable suppression by CD4+CD25high regulatory cells. Unlike CTLA4 blockade, blocking the interaction of PD-1 with its ligand PD-L1 affects the level of suppression. However, since this reduction in suppression by alphaPD-L1 can be overcome by increasing the number of CD4+CD25high T cells in the co-culture assay, the mechanism of CD4-CD25high regulation can proceed in the absence of PD-1/PD-L1 interactions, although it is not as efficient.
Baecher-Allan
Clare
C
Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Brown
Julia A
JA
Freeman
Gordon J
GJ
Hafler
David A
DA
D015703:Antigens, CD / Q000097:blood; D015704:CD4 Antigens / Q000097:blood*; D015496:CD4-Positive T-Lymphocytes / Q000145:classification / Q000276:immunology*; D018929:Cell Culture Techniques / Q000379:methods; D016207:Cytokines / Q000097:blood; D017931:DNA Primers; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D016133:Polymerase Chain Reaction; D015375:Receptors, Interleukin-2 / Q000097:blood* / Q000235:genetics*; D013601:T-Lymphocytes / Q000145:classification / Q000276:immunology*
D015703:Antigens, CD; D015704:CD4 Antigens; D016207:Cytokines; D017931:DNA Primers; D007376:Interleukin-2; D015375:Receptors, Interleukin-2