Peptide-specific CD8 T regulatory cells use IFN-gamma to elaborate TGF-beta-based suppression.
We identified a murine peptide-specific CD8 T regulatory cell population able to suppress responding CD4 T cells. Immunization with OVA, poly(I:C), and anti-4-1BB generated a population of SIINFEKL-specific CD8 T regulatory cells that profoundly inhibited peptide-responding CD4 T cells from cellular division. The mechanism of suppression required IFN-gamma, but IFN-gamma alone was not sufficient to suppress the responding CD4 T cells. The data show that CD8 T regulatory cells were unable to suppress unless they engaged IFN-gamma. Furthermore, even in the absence of recall with peptide, the CD8 T regulatory cells suppressed CD4 responses as long as IFN-gamma was present. To examine the effector mechanism of suppression, we showed that neutralizing TGF-beta inhibited suppression because inclusion of anti-TGF-beta rescued the proliferative capacity of the responding cells. TGF-beta-based suppression was dependent completely upon the CD8 T regulatory cells being capable of binding IFN-gamma. This was the case, although peptide recall of primed IFN-gamma (-/-) or IFN-gammaR(-/-) CD8 T cells up-regulated pro-TGF-beta protein as measured by surface latency-associated peptide expression but yet were unable to suppress. Finally, we asked whether the CD8 T regulatory cells were exposed to active TGF-beta in vivo and showed that only wild-type CD8 T regulatory cells expressed the TGF-beta-dependent biomarker CD103, suggesting that latency-associated peptide expression is not always congruent with elaboration of active TGF-beta. These data define a novel mechanism whereby IFN-gamma directly stimulates CD8 T regulatory cells to elaborate TGF-beta-based suppression. Ultimately, this mechanism may permit regulation of pathogenic Th1 responses by CD8 T regulatory cells.
Myers
Lara
L
Division of Immunology, University of Connecticut Health Center, Farmington, CT 06032, USA.
Croft
Michael
M
Kwon
Byoung S
BS
Mittler
Robert S
RS
Vella
Anthony T
AT
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004527:Egg Proteins / Q000008:administration & dosage / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology*; D039001:Integrin alpha Chains / Q000096:biosynthesis; D007371:Interferon-gamma / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology*; D010446:Peptide Fragments; D011485:Protein Binding / Q000276:immunology; D017471:Receptors, Interferon / Q000378:metabolism / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D000096743:Interferon gamma Receptor
D015703:Antigens, CD; D004527:Egg Proteins; D018984:Epitopes, T-Lymphocyte; D039001:Integrin alpha Chains; D007371:Interferon-gamma; D008024:Ligands; D010047:Ovalbumin; D010446:Peptide Fragments; D017471:Receptors, Interferon; D016212:Transforming Growth Factor beta; D000096743:Interferon gamma Receptor; C110366:OVA-8; C091367:alpha E integrins