TY - JOUR
T1 - BCAP links IL-1R to the PI3K-mTOR pathway and regulates pathogenic Th17 cell differentiation
AU - Deason, Krystin
AU - Troutman, Ty Dale
AU - Jain, Aakanksha
AU - Challa, Dilip K.
AU - Mandraju, Rajakumar
AU - Brewer, Travis
AU - Ward, E. Sally
AU - Pasare, Chandrashekhar
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (AI113125 and AI123176) to C. Pasare. K. Deason is supported by American Heart Association grant 17PRE33410075. The authors declare no competing financial interests.
Publisher Copyright:
© 2018 Deason et al.
PY - 2018
Y1 - 2018
N2 - The toll-like receptor (TLR) and interleukin (IL)-1 family of receptors share several signaling components, including the most upstream adapter, MyD88. We previously reported the discovery of B cell adapter for phosphoinositide 3-kinase (BCAP) as a novel toll-IL-1 receptor homology domain-containing adapter that regulates inflammatory responses downstream of TLR signaling. Here we find that BCAP plays a critical role downstream of both IL-1 and IL-18 receptors to regulate T helper (Th) 17 and Th1 cell differentiation, respectively. Absence of T cell intrinsic BCAP did not alter development of naturally arising Th1 and Th17 lineages but led to defects in differentiation to pathogenic Th17 lineage cells. Consequently, mice that lack BCAP in T cells had reduced susceptibility to experimental autoimmune encephalomyelitis. More importantly, we found that BCAP is critical for IL-1R-induced phosphoinositide 3-kinase-Akt-mechanistic target of rapamycin (mTOR) activation, and minimal inhibition of mTOR completely abrogated IL-1β-induced differentiation of pathogenic Th17 cells, mimicking BCAP deficiency. This study establishes BCAP as a critical link between IL-1R and the metabolic status of activated T cells that ultimately regulates the differentiation of inflammatory Th17 cells.
AB - The toll-like receptor (TLR) and interleukin (IL)-1 family of receptors share several signaling components, including the most upstream adapter, MyD88. We previously reported the discovery of B cell adapter for phosphoinositide 3-kinase (BCAP) as a novel toll-IL-1 receptor homology domain-containing adapter that regulates inflammatory responses downstream of TLR signaling. Here we find that BCAP plays a critical role downstream of both IL-1 and IL-18 receptors to regulate T helper (Th) 17 and Th1 cell differentiation, respectively. Absence of T cell intrinsic BCAP did not alter development of naturally arising Th1 and Th17 lineages but led to defects in differentiation to pathogenic Th17 lineage cells. Consequently, mice that lack BCAP in T cells had reduced susceptibility to experimental autoimmune encephalomyelitis. More importantly, we found that BCAP is critical for IL-1R-induced phosphoinositide 3-kinase-Akt-mechanistic target of rapamycin (mTOR) activation, and minimal inhibition of mTOR completely abrogated IL-1β-induced differentiation of pathogenic Th17 cells, mimicking BCAP deficiency. This study establishes BCAP as a critical link between IL-1R and the metabolic status of activated T cells that ultimately regulates the differentiation of inflammatory Th17 cells.
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U2 - 10.1084/jem.20171810
DO - 10.1084/jem.20171810
M3 - Article
C2 - 30093533
AN - SCOPUS:85057360048
SN - 0022-1007
VL - 215
SP - 2413
EP - 2428
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 9
ER -