PLoS Biology (Mar 2021)

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

  • Anand Sripada,
  • Kapil Sirohi,
  • Lidia Michalec,
  • Lei Guo,
  • Jerome T McKay,
  • Sangya Yadav,
  • Mukesh Verma,
  • James Good,
  • Donald Rollins,
  • Magdalena M Gorska,
  • Rafeul Alam

DOI
https://doi.org/10.1371/journal.pbio.3001063
Journal volume & issue
Vol. 19, no. 3
p. e3001063

Abstract

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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.