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 ϩ 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.

CD8+ CD122+ PD-1− effector cells promote the development of diabetes in NOD mice

“…Single-cell suspensions were prepared from the thymus, spleen, peripheral lymph nodes, and peripancreatic lymph nodes, as described previously [24]. The pancreas was dissected from the peripancreatic lymph nodes and cut into pieces.…”

Adaptor regulation of LFA‐1 signaling in T lymphocyte migration: Potential druggable targets for immunotherapies?

“…They contain various protein‐binding modules that link together multiple molecules and facilitate the creation of large signaling complexes. While transmembrane adaptors, including LAT, LIME, PAG, SIT, TRIM, and LAX are important in inside‐out signaling leading to LFA‐1 activation , cytoplasmic adaptors, such as talin1, kindlins, STAT3, CG‐NAP/AKAP‐450, adhesion and degranulation‐promoting adapter protein (ADAP), and Jun activation domain‐binding protein 1 (JAB‐1) play a pivotal role in LFA‐1‐mediated outside‐in signaling . Specificity in signaling facilitated by cytoplasmic adaptors is dictated by the type of protein‐binding modules, the sequence of domains or motifs, as well as the subcellular localization and proximity of binding partners.…”