Defective thymocyte maturation by transgenic expression of a truncated form of the T lymphocyte adapter molecule and Fyn substrate, Sin

Adapter molecules that promote protein-protein interactions play a central role in T lymphocyte differentiation and activation. In this study, we examined the role of the T lymphocyte-expressed adapter protein and Src kinase substrate, Sin, on thymocyte function using transgenic mice expressing an activated, truncated allele of Sin (SinΔC). We found that SinΔC expression led to reduced numbers of CD4⁺ and CD8⁺ single-positive cells and reduced thymic cellularity due to increased thymocyte apoptosis. Because the adapter properties of Sin are mediated by tyrosine-based motifs and given that Sin is a substrate for Src tyrosine kinases, we examined the involvement of these kinases in the inhibitory effects of SinΔC. We found that in transgenic thymocytes, SinΔC was constitutively phosphorylated by the Src kinase Fyn, but not by the related kinase Lck. Using SinΔC and fyn^-/- animals, we also found that the expression of Fyn was required for the inhibitory effect of SinΔC on thymocyte apoptosis but not for SinΔC-mediated inhibition of T cell maturation. The inhibitory effect of SinΔC on thymocyte maturation correlated with defective activation of the mitogen-activated protein kinase extracellular signal-regulated kinase. Our results suggest that the Sin mutant inhibits thymocyte differentiation through Fyn-dependent and -independent mechanisms and that endogenous Sin may be an important regulator of thymocyte development.