title: Endogenous CD4+BV8S2- T cells from TG BV8S2+ donors confer complete protection against spontaneous experimental encephalomyelitis (Sp-EAE) in TCR transgenic, RAG-/- mice.
abstract: To investigate regulatory mechanisms which naturally prevent autoimmune diseases, we adopted the genetically restricted immunodeficient (RAG-1(-/-)) myelin basic protein (MBP)-specific T cell receptor (TCR) double transgenic (T/R-) mouse model of spontaneous experimental autoimmune encephalomyelitis (Sp-EAE). Sp-EAE can be prevented after transfer of CD4+splenocytes from naïve immunocompetent mice. RAG-1+ double transgenic (T/R+) mice do not develop Sp-EAE due to the presence of a very small population (about 2%) of non-Tg TCR specificities. In this study, CD4+BV8S2+ T cells that predominate in T/R+ mice, and three additional populations, CD4+BV8S2-, CD4-CD8-BV8S2+, and CD4-CD8+BV8S2+ T cells that expanded in T/R+ mice after immunization with MBP-Ac1-11 peptide, were studied for their ability to prevent Sp-EAE in T/R- mice. Only the CD4+BV8S2- T cell population conferred complete protection against Sp-EAE, similar to unfractionated splenocytes from non-Tg donors, whereas CD4-CD8-BV8S2+ and CD4+BV8S2+ T cells conferred partial protection. In contrast, CD4-CD8+BV8S2+ T cells had no significant protective effects. The highly protective CD4+BV8S2- subpopulation was CD25+, contained non-clonotypic T cells, and uniquely expressed the CCR4 chemokine receptor. Protected recipient T/R- mice had marked increases in CD4+CD25+ Treg-like cells, retention of the pathogenic T cell phenotype in the spleen, and markedly reduced inflammation in CNS tissue. Partially protective CD4+BV8S2+ and CD4- CD8-BV8S2+ subpopulations appeared to be mainly clonotypic T cells with altered functional properties. These three Sp-EAE protective T cell subpopulations possessed distinctive properties and induced a variety of effects in T/R- recipients, thus implicating differing mechanisms of protection.
authors.affiliation: Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Agata
authors.initials: A
authors.lastname: Matejuk
authors.forename: Abigail C
authors.initials: AC
authors.lastname: Buenafe
authors.forename: Jami
authors.initials: J
authors.lastname: Dwyer
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ito
authors.forename: Marc
authors.initials: M
authors.lastname: Silverman
authors.forename: Alex
authors.initials: A
authors.lastname: Zamora
authors.forename: Sandhya
authors.initials: S
authors.lastname: Subramanian
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology* / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D018925:Chemokines / Q000096:biosynthesis; D004254:DNA Nucleotidyltransferases / Q000172:deficiency / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D007116:Immunization, Passive; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000276:immunology; D010446:Peptide Fragments / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D045522:Recombinases; D013116:Spinal Cord / Q000473:pathology; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D018925:Chemokines; D018398:Homeodomain Proteins; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019707:Receptors, Chemokine; D045522:Recombinases; C109168:T-cell receptor Vbeta 8.2; C405722:myelin basic protein 1-11; C064658:RAG-1 protein; D004254:DNA Nucleotidyltransferases