title: Self-peptides prolong survival in murine autoimmunity via reduced IL-2/IL-7-mediated STAT5 signaling, CD8 coreceptor, and V alpha 2 down-regulation.
abstract: Although the pathogenic role of B cells and CD4 T cells has been studied extensively, less is known about the role of CD8 T cells in autoimmunity and self-tolerance. To evaluate the role of CD8 T cells in autoimmunity and its modulation using self-peptides, we used mice expressing soluble OVA (sOVA) under control of the keratin-14 promoter. Spontaneous autoimmunity occurred when sOVA mice were crossed with OT-I mice, whose CD8 T cells carry a Valpha2/Vbeta5-transgenic TCR with specificity for the OVA(257-264) peptide. Eighty-three percent of OVA/OT-I mice died during the first 2 wk of life due to multiple organ inflammation. In contrast, preventive or therapeutic OVA(257-264) peptide injections induced a dose-dependent increase in survival. Healthy survivors exhibited reductions in peripheral CD8 T cells, CD8 coreceptor, and Valpha2 expression. Furthermore, CD8 T cells from healthy mice were anergic and could not be activated by exogenous IL-2. A block in IL-2/IL-7 signaling via the STAT5 pathway provided the basis for low surface expression of the CD8 coreceptor and failure of IL-2 to break CD8 T cell anergy. Thus, the soluble TCR ligand triggered multiple tolerance mechanisms in these sOVA/OT-I mice, making this treatment approach a potential paradigm for modulating human autoimmune diseases.
authors.affiliation: Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Gutermuth
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Nograles
authors.forename: Fumi
authors.initials: F
authors.lastname: Miyagawa
authors.forename: Emily
authors.initials: E
authors.lastname: Nelson
authors.forename: Young-Hun
authors.initials: YH
authors.lastname: Cho
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Katz
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D016827:CD8 Antigens / Q000378:metabolism; D002645:Chickens; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000235:genetics; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D015851:Interleukin-7 / Q000037:antagonists & inhibitors* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D012995:Solubility; D016019:Survival Analysis
chemical_list: D016827:CD8 Antigens; C067361:CD8 receptor; D007376:Interleukin-2; D015851:Interleukin-7; C110366:OVA-8; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D050799:STAT5 Transcription Factor; D010047:Ovalbumin
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