Essential Role of LAT in T Cell Development

Abstract

The linker molecule LAT is a substrate of the tyrosine kinases activated following TCR engagement. Phosphorylated LAT binds many critical signaling molecules. The central role of this molecule in TCR-mediated signaling has been demonstrated by experiments in a LAT-deficient cell line. To probe the role of LAT in T cell development, the LAT gene was disrupted by targeting. LAT-deficient mice appeared healthy. Flow cytometric analysis revealed normal B cell populations but the absence of any mature peripheral T cells. Intrathymic development was blocked within the CD4- CD8- stage. No gross abnormality of NK or platelet function was observed. LAT is thus critical to both T cell activation and development.

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

“…48,49 LAT encodes a transmembrane adaptor protein with a role in the development, activation, and maintenance of T cells. 34 It is modulated by CD247 and ZAP70 tyrosine phosphorylation upon TCR activation and controls signal diversification and amplification. 50 Consistent with this observation, overexpression of these two genes phenocopies the overexpression of LAT, i.e., decreases cell proliferation in the zebrafish developing brain.…”

“…34 Mouse brain samples were perfused and post fixed in 4% PFA for 48 hr. Sixty-three brain parameters (area and length measurements) were measured blind to the genotype across two coronal sections (Bregma 0.98 mm and À1.34 mm) as described 35 and data were analyzed using a Student two-tailed equal variance test.…”

“…As a further test of the specificity of the phenotypes induced by the LAT candidate and the neuroanatomical changes observed in teleosts, we studied the neuroanatomy of the established Lat knockout mouse, 34 a model generated originally to study the well-known role of Lat in immunity 34 but for which, to our knowledge, its role during the brain development was never assessed.…”

Peripheral Thy1+ lymphocytes rearranging TCR‐γδ genes in LAT‐deficient mice

“…However, physiological roles of LAT adaptor in these cell lineages seem variable. In LAT knockout mice, NK lymphocytes, megakaryocytes and mast cells show seemingly normal development [8] with only discrete deficiencies of particular signaling pathways [5][6][7]. During B-cell maturation LAT deficiency causes a partial developmental block at the pre-B-cell stage [9,10].…”

“…During B-cell maturation LAT deficiency causes a partial developmental block at the pre-B-cell stage [9,10]. In contrast, development of ab and gd T cells is entirely dependent on LAT adaptor, which is essential for signaling at the pre-TCR and ''TCR-gd quality control'' checkpoints [8,11]. Neither ab nor gd T cells have previously been found to develop and/or colonize the periphery of LAT knockout mice.…”