title: SLAT/Def6 plays a critical role in the pathogenic process of experimental autoimmune uveitis (EAU).
abstract: OBJECTIVE
  SWAP 70-like adaptor of T cells (SLAT; aka Def6) is a recently discovered guanine nucleotide exchange factor for Rho guanosine triphosphate (GTP)ases that has been previously shown to play a role in cluster of differentiation(CD)4+ T cell activation, T-helper (Th)1/Th2/Th17 differentiation and development of experimental autoimmune encephalomyelitis. Here, we investigated the role of SLAT/Def6 in the development of experimental autoimmune uveitis (EAU), an animal model for several uveitic conditions in humans.
  
  
  METHODS
  SLAT/Def6 deficient ("KO") mice and C57BL/6 controls were immunized with interphotoreceptor retinoid-binding protein (IRBP), along with pertussis toxin. The development of ocular inflammation was determined by both fundoscopy and histological examination. Lymphoid cells from draining lymph nodes were cultured with IRBP to measure lymphocyte proliferation and release of cytokines. Purified dendritic cells were tested for their capacity to present antigen to responding lymphocytes. In addition, the lymphoid cells were tested for the expression of forkhead box P3 (FoxP3), using conventional methods, and the activity of T-regulatory cells was determined by their capacity to inhibit in vitro proliferative responses. Serum anti -IRBP antibody levels were measured by enzyme-linked immunosorbant assay (ELISA). quantitative polymerase chain reaction (qPCR) was used to determine the transcript levels of cytokines in inflamed eyes.
  
  
  RESULTS
  SLAT/Def6 KO mice had significantly reduced EAU compared to controls. Cells isolated from draining lymph nodes of SLAT/Def6 KO mice exhibited impaired proliferation and production of Th1 and Th17 signature cytokines (interferon [IFN]-γ and interleukin [IL]-17, respectively) when compared with cells isolated from control mice. qPCR of inflamed eyes detected similar levels of IFN-γ transcript in control and SLAT/Def6 KO mice, whereas the IL-17 transcript levels in eyes of the SLAT/Def6 KO mice were lower than in eyes of the controls. The SLAT/Def6 KO mice resembled their wild type (WT) controls, however, in the levels of their serum antibody against IRBP, the antigen presenting capacity of their dendritic cells, the proportion of cells expressing Foxp3 and the immunosuppressive activity of their T-regulatory cells.
  
  
  CONCLUSIONS
  SLAT/Def6 KO mice exhibit reduced capacity to develop ocular inflammation and cellular activity when immunized with IRBP. Our study provides new data showing that SLAT/Def6 plays a major role in the T cell-mediated autoimmune processes that bring about the inflammatory eye disease, EAU.
authors: Laboratory of Immunology, National Eye Institute/NIH, 10 Center Drive, Bethesda, MD 20892, USA.
authors: Barbara P
authors: BP
authors: Vistica
authors: Guangpu
authors: G
authors: Shi
authors: Lindsey
authors: L
authors: Nugent
authors: Cuiyan
authors: C
authors: Tan
authors: Amnon
authors: A
authors: Altman
authors: Igal
authors: I
authors: Gery
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood / Q000276:immunology; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000008:administration & dosage / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000276:immunology; D020662:Guanine Nucleotide Exchange Factors; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D037342:Pertussis Toxin / Q000008:administration & dosage; D012177:Retinol-Binding Proteins / Q000008:administration & dosage / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014605:Uveitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D000906:Antibodies; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D051858:Forkhead Transcription Factors; D020662:Guanine Nucleotide Exchange Factors; D007371:Interferon-gamma; D020381:Interleukin-17; D009687:Nuclear Proteins; D037342:Pertussis Toxin; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial; C498833:Foxp3 protein, mouse; C473249:Def6 protein, mouse