title: The Importance of IL-6 in the Development of LAT-Mediated Autoimmunity.
abstract: Linker for activation of T cells (LAT) is a transmembrane adaptor protein that is highly tyrosine phosphorylated upon engagement of the TCR. Phosphorylated LAT binds Grb2, Gads, and phospholipase C (PLC)γ1 to mediate T cell activation, proliferation, and cytokine production. T cells from mice harboring a mutation at the PLCγ1 binding site of LAT (Y136F) have impaired calcium flux and Erk activation. Interestingly, these T cells are highly activated, resulting in the development of a lymphoproliferative syndrome in these mice. CD4(+) T cells in LATY136F mice are Th2 skewed, producing large amounts of IL-4. In this study, we showed that the LATY136F T cells could also overproduce IL-6 due to activated NF-κB, AKT, and p38 pathways. By crossing LATY136F mice with IL-6-deficient mice, we demonstrated that IL-6 is required for uncontrolled T cell expansion during the early stage of disease development. Reduced CD4(+) T cell expansion was not due to a further block in thymocyte development or an increase in the number of regulatory T cells, but was caused by reduction in cell survival. In aged IL-6(-/-) LATY136F mice, CD4(+) T cells began to hyperproliferate and induced splenomegaly; however, isotype switching and autoantibody production were diminished. Our data indicated that the LAT-PLCγ1 interaction is important for controlling IL-6 production by T cells and demonstrated a critical role of IL-6 in the development of this lymphoproliferative syndrome.
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: O'Brien
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Minghua
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710 zhang033@mc.duke.edu.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015551:Autoimmunity; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D005786:Gene Expression Regulation; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D017136:Ion Transport; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D051966:Phospholipase C gamma / Q000235:genetics / Q000276:immunology*; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology*; D061251:Primary Cell Culture; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015850:Interleukin-6; C491734:Lat protein, mouse; D008565:Membrane Proteins; D016328:NF-kappa B; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D051966:Phospholipase C gamma; C117399:Plcg1 protein, mouse; D002118:Calcium