SLy1 regulates T‐cell proliferation during Listeria monocytogenes infection in a Foxo1‐dependent manner

Infection of mice with Listeria monocytogenes results in a strong T‐cell response that is critical for an efficient defense. Here, we demonstrate that the adapter protein SLy1 (SH3‐domain protein expressed in Lymphocytes 1) is essential for the generation of a fully functional T‐cell response. The lack of SLy1 leads to reduced survival rates of infected mice. The increased susceptibility of SLy1 knock‐out (KO) mice was caused by reduced proliferation of differentiated T cells. Ex vivo analyses of isolated SLy1 KO T cells displayed a dysregulation of Forkhead box protein O1 shuttling after TCR signaling, which resulted in an increased expression of cell cycle inhibiting genes, and therefore, reduced expansion of the T‐cell population. Forkhead box protein O1 shuttles to the cytoplasm after phosphorylation in a protein complex including 14‐3‐3 proteins. Interestingly, we observed a similar regulation for the adapter protein SLy1, where TCR stimulation results in SLy1 phosphorylation and SLy1 export to the cytoplasm. Moreover, immunoprecipitation analyses revealed a binding of SLy1 to 14‐3‐3 proteins. Altogether, this study describes SLy1 as an immunoregulatory protein, which is involved in the generation of adaptive immune responses during L. monocytogenes infection, and provides a model of how SLy1 regulates T‐cell proliferation.