Complementation in trans of altered thymocyte development in knock-in mice expressing mutant forms of SLP76

• Published in: Immunity (Cambridge, Mass.) Vol. 28; no. 3; pp. 359 - 369
• Main Authors: Jordan, Martha S., Smith, Jennifer E., Burns, Jeremy C., Austin, Jessica-Elise T., Nichols, Kim E., Aschenbrenner, Anna C., Koretzky, Gary A.
• Format: Journal Article
• Language: English
• Published: 01-03-2008
• ISSN: 1074-7613
• DOI: 10.1016/j.immuni.2008.01.010

The adaptor protein SLP76 directs signaling downstream of the TCR and is essential for thymocyte development. SLP76 contains three tyrosines in its N-terminus that are critical for its function. To define the role of these residues in thymocyte development, we generated two lines of KI mice, one expressing a mutation in tyrosine 145 (Y145F) and a second harboring two point mutations at tyrosines 112 and 128 (Y112/128F). We show here that while thymocyte development requires both Y145 and Y112/128-generated signals, selection is more dependent upon Y145. While several proximal TCR signaling events were defective in both KI mice, phosphorylation of Vav1 and activation of Itk-dependent pathways were differentially affected by mutations at Y112/128 or Y145, respectively. Analysis of mice expressing one Y145F and one Y112/128F allele revealed that these mutants could complement one another
in trans
, demonstrating cooperativity between two or more SLP76 molecules.