Origins and functional basis of regulatory CD11c+CD8+ T cells.
Previously, we showed that CD11c defines a novel subset of CD8(+) T cells whose in vivo activity is therapeutic for arthritis; however, the mechanisms directing their development, identity of their precursors, and basis of their effector function remain unknown. Here, we show that the novel subset develops from CD11c(surface-)CD8(+) T cells and undergoes robust expansion in an antigen- and 4-1BB (CD137)-dependent manner. CD11c(+)CD8(+) T cells exist in naïve mice (<3%) with limited suppressive activity. Once activated, they suppress CD4(+) T cells in vivo and in vitro. Suppression of CD4(+) by CD11c(+)CD8(+) T cells is related to an increase in IDO activity induced in competent cells via the general control non-derepressible-2 pathway. CD11c(+)CD8(+) T cells are refractory to the effect of IDO but constrict in a novel 1-methyl D,L-tryptophan-dependent mechanism resulting in reversal of their suppressive effects. Thus, our data uncover, for the first time, the origin, development, and basis of the suppressive function of this novel CD11c(+)CD8(+) T-cell subpopulation that has many signature features of Treg.
Vinay
Dass S
DS
Section of Clinical Immunology, Allergy, and Rheumatology, Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA.
Kim
Chang H
CH
Choi
Beom K
BK
Kwon
Byoung S
BS
D000818:Animals; D039521:CD11c Antigen / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology*; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000628:therapy; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D007108:Immune Tolerance / Q000276:immunology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D051742:Transcription Factor CHOP / Q000378:metabolism; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000276:immunology
D039521:CD11c Antigen; C497250:Ddit3 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C110366:OVA-8; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D051742:Transcription Factor CHOP; D014364:Tryptophan; D010047:Ovalbumin; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases