T Cell Intrinsic BCAP Links IL1R to the PI3K-mTOR Pathway and Regulates Pathogenic Th17 Differentiation

Toll-IL-1R homology (TIR) domains are found within adaptor proteins involved in the signaling of Toll like receptors (TLRs) and Interleukin 1 receptor (IL1R) families. Previous work by our lab identified a TIR domain in the protein B cell adaptor for phosphoinositide 3-kinase (BCAP) and determined a role for BCAP in the TLR signaling pathway in myeloid cells. Due to the shared use of TIR domains by TLR and IL1R signaling pathways, I hypothesized that BCAP would also be involved in signaling downstream of the IL1 family of receptors. The IL1 cytokine family has been shown to play a major role in T cell activation, survival, and differentiation; IL1b, in particular, plays a critical role in the differentiation of Th17 lineage cells. Here, I discovered that BCAP functions downstream of IL1R in CD4 T cells and thereby regulates Th17 lineage differentiation and function. IL1b-induced PI3K-Akt-mTOR signaling is compromised in BCAP deficient T cells which leads to decreased mTOR activation, decreased glycolysis, and defective Th17 lineage commitment. Transcriptional analysis of BCAP deficient CD4 T cells revealed that BCAP is critical for the expression of genes associated with pathogenic Th17 lineage cells. Mice specifically lacking BCAP in T cells have normal development of steady state Th17 cells in vivo yet have decreased development of pathogenic Th17 diseases, such as experimental autoimmune encephalomyelitis (EAE) and T cell transfer colitis. Further, the use of a potent inhibitor of mTOR, which is downstream of BCAP activation, mimics BCAP deficiency by preventing IL1b induced differentiation of pathogenic Th17 cells. This study establishes BCAP as a critical link between IL1R and the metabolic status of activated Th17 cells and further demonstrates that BCAP is critical for the generation of pathogenic Th17 cells in vitro and in vivo.

Author dc:creator

• Deason, Krystin Leigh

Contributors dc:contributor

• Hooper, Lora V.
• Pasare, Chandrashekhar
• van Oers, Nicolai S. C.
• Satterthwaite, Anne B.

• Adaptor Proteins, Signal Transducing
• Cell Differentiation
• Phosphatidylinositol 3-Kinases
• Receptors, Interleukin-1
• Signal Transduction
• TOR Serine-Threonine Kinases
• Th17 Cells

Language dc:language

en

Identifier

1192325703

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/8800