Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism.
CD4+CD25+ regulatory T cells (Treg) are potent immunosuppressive cells that are pivotal in the regulation of peripheral tolerance. In this report, we identify granzyme B (GZ-B) as one of the key components of Treg-mediated suppression. Induction of regulatory activity is correlated with the up-regulation of GZ-B expression. Proof of a functional involvement of GZ-B in contact-mediated suppression by Treg is shown by the reduced ability of Treg from GZ-B-/- mice to suppress as efficiently as Treg from WT mice. GZ-B-mediated suppression is perforin independent, because suppression by Treg from perforin-/- and WT is indistinguishable. Additionally, suppression mediated by Treg appears to be mediated, in part, by the induction of apoptosis in the CD4+CD25- effector cell. In summary, GZ-B is one of the key mechanisms through which CD4+CD25+ Treg induce cell contact-mediated suppression.
Gondek
David C
DC
Department of Microbiology and Immunology, Dartmouth Medical School and Norris Cotton Cancer Center, Lebanon, NH 03756, USA.
Lu
Li-Fan
LF
Quezada
Sergio A
SA
Sakaguchi
Shimon
S
Noelle
Randolph J
RJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D002450:Cell Communication / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D053450:Glucocorticoid-Induced TNFR-Related Protein; D053804:Granzymes; D007106:Immune Sera / Q000494:pharmacology; D007165:Immunosuppression Therapy / Q000379:methods; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D017475:Receptors, Nerve Growth Factor / Q000276:immunology / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000502:physiology; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*
D053450:Glucocorticoid-Induced TNFR-Related Protein; D007106:Immune Sera; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D015842:Serine Proteinase Inhibitors; C106544:Tnfrsf18 protein, mouse; D054353:Perforin; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases