Open AccessSprouty2 positively regulates T cell function and airway inflammation through regulation of CSK and LCK kinases
Author(s) -
Anand Sripada,
Kapil Sirohi,
Lidia Michalec,
Lei Guo,
Jerome T McKay,
Sangya Yadav,
Mukesh Verma,
James T. Good,
Donald Rollins,
M. Górska,
Rafeul Alam
Publication year - 2021
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3001063
Subject(s) - biology , microbiology and biotechnology , kinase , gene knockdown , signal transduction , inflammation , cytokine , cancer research , immunology , cell culture , genetics
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.