BCAP links IL-1R to the PI3K-mTOR pathway and regulates pathogenic Th17 cell differentiation

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Toll-like receptor (TLR) and interleukin (IL)-1 family receptors utilize shared signaling adaptors like MyD88.
• B cell adapter for phosphoinositide 3-kinase (BCAP) was previously identified as a regulator of TLR-mediated inflammatory responses.

Purpose of the Study:

• To investigate the role of BCAP in T helper cell differentiation downstream of IL-1 and IL-18 receptors.
• To elucidate the molecular mechanisms by which BCAP influences pathogenic T helper 17 cell differentiation and experimental autoimmune encephalomyelitis.

Main Methods:

• Analysis of T cell-specific BCAP knockout mice.
• Assessment of T helper cell differentiation in vitro and in vivo.
• Investigation of the phosphoinositide 3-kinase-Akt-mechanistic target of rapamycin (mTOR) pathway activation.

Main Results:

• BCAP is essential for T helper 17 and T helper 1 cell differentiation downstream of IL-1 and IL-18 receptors, respectively.
• T cell-intrinsic BCAP deficiency impairs differentiation into pathogenic Th17 cells, reducing susceptibility to experimental autoimmune encephalomyelitis.
• BCAP is critical for IL-1 receptor-mediated activation of the PI3K-Akt-mTOR pathway, and mTOR inhibition phenocopies BCAP deficiency in Th17 differentiation.

Conclusions:

• BCAP acts as a key adapter linking IL-1 receptor signaling to T cell metabolic reprogramming.
• BCAP regulates the differentiation of inflammatory Th17 cells by influencing the PI3K-Akt-mTOR pathway.
• Targeting BCAP or the mTOR pathway may offer therapeutic strategies for inflammatory diseases driven by pathogenic Th17 cells.