Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adoptive Transfer
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Analysis of Variance
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Animals
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CD8 Antigens / metabolism
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / transplantation
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Cytokines / metabolism
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / metabolism*
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Enzyme-Linked Immunosorbent Assay
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Female
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Forkhead Transcription Factors / metabolism
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Glycoproteins / immunology
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Interferon gamma Receptor
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Interferon-gamma / genetics
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Interferon-gamma / metabolism*
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Interleukin-2 Receptor alpha Subunit / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Inbred Strains
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Mice, Knockout
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Myelin Proteins
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Myelin-Associated Glycoprotein / chemistry
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Myelin-Associated Glycoprotein / immunology
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments / immunology
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Receptors, Interferon / genetics
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Receptors, Interferon / metabolism
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism*
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T-Lymphocytes, Regulatory / transplantation
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism*
Substances
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CD8 Antigens
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Cytokines
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Glycoproteins
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Interleukin-2 Receptor alpha Subunit
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Mog protein, mouse
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Myelin Proteins
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Myelin-Associated Glycoprotein
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments
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Receptors, Interferon
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Transforming Growth Factor beta
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myelin oligodendrocyte glycoprotein (35-55)
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Interferon-gamma