Sprouty2 positively regulates T cell function and airway inflammation through regulation of CSK and LCK kinases

The function of Sprouty2 (Spry2) in T cells is unknown. Using 2 different (inducible and T cell–targeted) knockout mouse strains, we found that Spry2 positively regulated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling by modulating the activity of LCK. Spry2^−/− CD4⁺ T cells were unable to activate LCK, proliferate, differentiate into T helper cells, or produce cytokines. Spry2 deficiency abrogated type 2 inflammation and airway hyperreactivity in a murine model of asthma. Spry2 expression was higher in blood and airway CD4⁺ T cells from patients with asthma, and Spry2 knockdown impaired human T cell proliferation and cytokine production. Spry2 deficiency up-regulated the lipid raft protein caveolin-1, enhanced its interaction with CSK, and increased CSK interaction with LCK, culminating in augmented inhibitory phosphorylation of LCK. Knockdown of CSK or dislodgment of caveolin-1–bound CSK restored ERK1/2 activation in Spry2^−/− T cells, suggesting an essential role for Spry2 in LCK activation and T cell function.

The ubiquitously expressed protein Sprouty2 (Spry2) is a known regulator of Ras/ERK signaling pathway. This study uses in vitro and in vivo models, as well as human specimens, to reveal a mechanism for Spry2 in positively regulating ERK activation in CD4+ T-cells.