title: Cooperative immunoregulatory function of the transmembrane adaptor proteins SIT and LAX.
abstract: Lymphocyte activation is crucial for the generation of immune responses. In vitro studies have demonstrated that TRAPs are critical regulators of lymphocyte activation. However, more recent in vivo studies have demonstrated that with the exception of LAT, TRAPs, such as SIT, NTAL, and LAX, only minimally affect immune cell functions. Additional studies have suggested that the mild or the apparent lack of a phenotype displayed by most TRAP KO mice may be explained by functional redundancy among this family of adaptors. In fact, it has been shown that the phenotype of NTAL/LAT or SIT/TRIM double-deficient mice is more severe than that of the single KOs. Here, we have evaluated whether SIT and the related transmembrane adaptor LAX have overlapping functions by generating SIT/LAX DKO mice. We show that DKO, in contrast to single KO mice, accumulate large numbers of activated CD4(+) T cells in the spleen. Moreover, conventional B cells from DKO mice are hyperproliferative upon CD40 stimulation. Additionally, we found that DKO mice displayed an expansion of the B1 cell pool in the peritoneal cavity, hypergammaglobulinaemia, and an enhanced immune response to the T1-independent antigen, TNP-LPS. Finally, we demonstrate that SIT/LAX double deficiency resulted in a more pronounced breakdown of peripheral tolerance and the development of autoimmunity characterized by ANAs and renal disease (glomerulonephritis and proteinuria). Collectively, our data indicate that SIT and LAX are important negative regulators of immune responses that functionally cooperate.
authors: Institutes of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany. boerge.arndt@med.uni-muenchen.de
authors: Börge
authors: B
authors: Arndt
authors: Thomas
authors: T
authors: Kalinski
authors: Dirk
authors: D
authors: Reinhold
authors: Anja
authors: A
authors: Thielitz
authors: Albert
authors: A
authors: Roessner
authors: Burkhart
authors: B
authors: Schraven
authors: Luca
authors: L
authors: Simeoni
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology*; D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology; D006942:Hypergammaglobulinemia / Q000235:genetics / Q000276:immunology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010529:Peritoneal Cavity; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D019013:CD40 Antigens; D007527:Isoenzymes; C501224:LAX protein, mouse; D008565:Membrane Proteins; C503874:SIT protein, mouse; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase