LAT, also known as linker for activation of T cells, is a crucial transmembrane adapter protein. It plays a key role in T-cell antigenic signaling, acting as a bridge between T-cell-specific and general signaling pathways. When T-cell receptors (TCRs) are engaged, LAT becomes tyrosine-phosphorylated, creating binding sites for various proteins and organizing a multiprotein signaling complex. This complex links the TCR to downstream pathways such as NFAT and AP-1, which are essential for T-cell activation, development, and function [1,2,3,4].

Studies using mouse models with mutant forms of LAT have provided insights into its role. Some mutant forms led to partial or complete inhibition of T-cell development, suggesting LAT as a positive regulator of TCR signaling. However, LAT "knock-ins" with point mutations in specific tyrosine residues developed lymphoproliferative disorders involving polyclonal T cells that produced high amounts of T helper-type 2 (Th2) cytokines, revealing its role as a negative regulator of TCR signaling and T-cell homeostasis [4,5].

In conclusion, LAT is essential for coordinating T-cell signaling events, regulating both T-cell development and homeostasis. Mouse models with LAT mutations have been instrumental in uncovering its dual-role as a positive and negative regulator in T-cell function, which is relevant to understanding immunopathology and potential immune-related diseases [4,5].

References:

1. Rubin, Adam J, Dao, Tyler T, Schueppert, Amelia V, Regev, Aviv, Shalek, Alex K. 2024. LAT encodes T cell activation pathway balance. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.08.26.609683. https://pubmed.ncbi.nlm.nih.gov/39253472/

2. Balagopalan, Lakshmi, Coussens, Nathan P, Sherman, Eilon, Samelson, Lawrence E, Sommers, Connie L. 2010. The LAT story: a tale of cooperativity, coordination, and choreography. In Cold Spring Harbor perspectives in biology, 2, a005512. doi:10.1101/cshperspect.a005512. https://pubmed.ncbi.nlm.nih.gov/20610546/

3. Wange, R L. 2000. LAT, the linker for activation of T cells: a bridge between T cell-specific and general signaling pathways. In Science's STKE : signal transduction knowledge environment, 2000, re1. doi:. https://pubmed.ncbi.nlm.nih.gov/11752630/

4. Malissen, Bernard, Aguado, Enrique, Malissen, Marie. . Role of the LAT adaptor in T-cell development and Th2 differentiation. In Advances in immunology, 87, 1-25. doi:. https://pubmed.ncbi.nlm.nih.gov/16102570/

5. Malissen, Bernard, Wang, Ying, Mingueneau, Michael, Malissen, Marie. . Th2 lymphoproliferative disorders resulting from defective LAT signalosomes. In Novartis Foundation symposium, 281, 93-100; discussion 100-2, 208-9. doi:. https://pubmed.ncbi.nlm.nih.gov/17534068/