Novel CD8+ Treg suppress EAE by TGF-beta- and IFN-gamma-dependent mechanisms.
Although CD8+ Treg-mediated suppression has been described, CD8+ Treg remain poorly characterized. Here we identify a novel subset of CD8+ Treg that express latency-associated peptide (LAP) on their cell surface (CD8+LAP+ cells) and exhibit regulatory activity in vitro and in vivo. Only a small fraction of CD8+LAP+ cells express Foxp3 or CD25, although the expression levels of Foxp3 for these cells are higher than their LAP- counterparts. In addition to TGF-beta, CD8+LAP+ cells produce IFN-gamma, and these cells suppress EAE that is dependent on both TGF-beta and IFN-gamma. In an adoptive co-transfer model, CD8+LAP+ cells suppress myelin oligodendrocyte glycoprotein (MOG)-specific immune responses by inducing or expanding Foxp3+ cells and by inhibiting proliferation and IFN-gamma production in vivo. Furthermore, in vivo neutralization of IFN-gamma and studies with IFN-gamma-deficient mice demonstrate an important role for IFN-gamma production in the function of CD8+LAP+ cells. Our findings identify the underlying mechanisms that account for the immunoregulatory activity of CD8+ T cells and suggest that induction or amplification of CD8+LAP+ cells may be a therapeutic strategy to help control autoimmune processes.
Chen
Mei-Ling
ML
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. mlingchen@rics.bwh.harvard.edu
Yan
Bo-Shiun
BS
Kozoriz
Deneen
D
Weiner
Howard L
HL
D019264:Adoptive Transfer; D000704:Analysis of Variance; D000818:Animals; D016827:CD8 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006023:Glycoproteins / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000737:chemistry / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D000096743:Interferon gamma Receptor
D016827:CD8 Antigens; D016207:Cytokines; D051858:Forkhead Transcription Factors; D006023:Glycoproteins; D007371:Interferon-gamma; D053645:Interleukin-2 Receptor alpha Subunit; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D017471:Receptors, Interferon; D016212:Transforming Growth Factor beta; D000096743:Interferon gamma Receptor; C498833:Foxp3 protein, mouse; C571327:Mog protein, mouse; C445081:myelin oligodendrocyte glycoprotein (35-55)