Cutting Edge: Responder T cells regulate human DR+ effector regulatory T cell activity via granzyme B.
MHC class II expression identifies an effector subset of human CD4(+)CD25(high)FoxP3(high) natural regulatory T cells (DR(+) Tregs) that induces more rapid suppression and exhibits higher FoxP3 expression than the remaining Treg population. Although Tregs are known to be highly sensitive to apoptosis, in this study we demonstrate that this sensitivity is primarily a feature of DR(+) Tregs. Granzyme B (GzmB) is strongly expressed by nonregulatory responder CD4 T cells, whereas effector DR(+) Tregs express little GzmB. Strong TCR stimulation markedly increases the expression of GzmB in all dividing responder CD4 T cells and mitigates the suppression by DR(+) Tregs. DR(+) Treg suppressive activity reemerges if GzmB is neutralized. We show that responder cells actively kill effector Tregs by producing GzmB in response to strong TCR stimulation. Thus, the production of GzmB by strongly activated CD4 T cells represents a mechanism by which CD4 T cells resist Treg suppression.
Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
Charles W
CW
Ashley
Clare
C
Baecher-Allan
D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D018801:CD2 Antigens / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D053804:Granzymes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D007155:Immunologic Factors / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D034741:RNA, Small Interfering / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*
D000911:Antibodies, Monoclonal; D018801:CD2 Antigens; D017252:CD3 Complex; D007155:Immunologic Factors; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D053804:Granzymes