Effector T cells driving monophasic vs. relapsing/remitting experimental autoimmune uveitis show unique pathway signatures.
Autoimmune diseases often show a relapsing-remitting course. Here we describe characteristics of the autoreactive T cell response in the Lewis rat model of experimental autoimmune uveitis (EAU), a model for the clinical heterogeneity seen in human uveitis. Depending on the autoantigen used, the experimental disease course can be either monophasic or relapsing/remitting. This appears to be dictated by subtle differences in the T cell effector phenotype elicited. Using transcriptomic profiling and pathway analysis, the molecular basis for the monophasic vs. relapsing/remitting effector T cell phenotype was investigated. CD4+ T cell lines specific for peptide R14 derived from interphotoreceptor retinoid-binding protein (IRBP), which mediate the relapsing disease, were compared to the monophasic disease-inducing lines responding to retinal S-antigen peptide PDSAg. Expression profiles from T cell lines representing each specificity were analyzed using Affymetrix microarrays. Differential gene expression was confirmed and extended by quantitative PCR and verified on the protein level. A set of genes was uniquely upregulated in the R14-specific T cells. Gene ontology analysis demonstrated that these genes were linked to regulatory pathways associated with antigen presentation, lymphocyte activation, regulation of apoptosis and WNT/Hedgehog signaling. R14-specific T cells were further demonstrated to have prolonged survival in vivo, and a Th1-dominated cytokine profile, while the PDSAg-specific T cells lines were more Th17-prone. Our findings suggest that the nature of specific antigens leads to subtle programming of the effector phenotype underlying recurrent inflammation.
von Toerne
Christine
C
Clin. Biochemistry, Medical Policlinic, Clinic of the Ludwig-Maximilians-University, Schillerstr. 42, 80336 Munich, Germany.
Sieg
Cornelia
C
Kaufmann
Ulrike
U
Diedrichs-Möhring
Maria
M
Nelson
Peter J
PJ
Wildner
Gerhild
G
D000818:Animals; D019393:Arrestin / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011917:Rats, Inbred Lew; D012177:Retinol-Binding Proteins / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014605:Uveitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000099214:Retinol-Binding Proteins, Interstitial
D019393:Arrestin; D001324:Autoantigens; D016207:Cytokines; D012177:Retinol-Binding Proteins; C487847:Rbp3 protein, rat; D000099214:Retinol-Binding Proteins, Interstitial