T‐cell activation RhoGTPase‐activating protein plays an important role in T_H17‐cell differentiation

Abstract

T-cell activation RhoGTPase-activating protein (TAGAP) is a GTPase-activating protein specific for RhoA that is exclusively expressed in activated T cells. Genome-wide association studies and metagenome SNPs analyses have indicated that TAGAP is associated with the pathogenesis of multiple autoimmune diseases, including psoriasis, rheumatoid arthritis, Crohn's disease, celiac disease and multiple sclerosis. However, the precise function of TAGAP remains unclear. Because T17 cells contribute to TAGAP-associated autoimmune diseases, we hypothesized that TAGAP plays key roles in the differentiation and/or function of T17 cells. To evaluate this hypothesis, we analyzed the effect of TAGAP on T17 differentiation in vitro and established a line of TAGAP-deficient mice. We found that TAGAP was required for T17 differentiation in vitro and that the loss of TAGAP in mice ameliorated the clinical features of experimental autoimmune encephalomyelitis, indicating that TAGAP is critical for disease progression. We also demonstrated that TAGAP interacts with RhoH, an adapter protein that interacts with lck and ZAP70 in proximal TCR signaling. TAGAP competes with ZAP70 for RhoH binding, thereby inhibiting TCR-associated signal transduction. Consistent with these findings, TCR-induced ERK activation was increased in TAGAP-deficient T cells. Because the upregulation of TCR signaling inhibits Th17 differentiation, TAGAP may prevent TCR signaling activity from reaching the limit of the induction of T17 cells. Collectively, our findings indicate that TAGAP is a novel factor required for T17-cell differentiation and that TAGAP potentially represents a novel target of autoimmune disease therapies.

Genome-scale comparative analysis for host resistance against sea lice between Atlantic salmon and rainbow trout

“…Thus, genes related with immune response, either by promoting leukocyte growth or favoring migration or activation are strong candidate genes. For instance, in Atlantic salmon we found T-cell activation Rho GTPase-activating protein (TAGAP) which participates in the activation and recruitment of T cells by cytokines 33 , and tenascin R (TNR) which is an extracellular matrix protein, present in bone marrow, thymus, spleen and lymph nodes 34 . The latter has been described as having an adhesin function favoring the mobility of lymphocytes and lymphoblasts 34,35 .…”

Differential T‐cell receptor signals for T helper cell programming

“…TAGAP inhibits the binding of Zap70 to the adapter RhoH, thereby reducing the strength of the TCR signal . Reduced Th17 differentiation was observed in TAGAP –/– T cells and this was associated with a milder experimental autoimmune encephalomyelitis (EAE) phenotype . These studies did not address differentiation of other Th cell subsets, or examine IL‐2 production, so it is not clear how this study fits into the body of work suggesting that high TCR signals are required for Th17 differentiation.…”

“…Several other signalling molecules have been implicated in Th cell subset differentiation, including Nck, MALT1, Pak2, Notch and other early components of the TCR signalling pathway . Another study identified a role for T‐cell activation RhoGTPase‐activating protein (TAGAP) in Th17 differentiation . TAGAP inhibits the binding of Zap70 to the adapter RhoH, thereby reducing the strength of the TCR signal .…”

“…Another study identified a role for T‐cell activation RhoGTPase‐activating protein (TAGAP) in Th17 differentiation . TAGAP inhibits the binding of Zap70 to the adapter RhoH, thereby reducing the strength of the TCR signal . Reduced Th17 differentiation was observed in TAGAP –/– T cells and this was associated with a milder experimental autoimmune encephalomyelitis (EAE) phenotype .…”

TAGAP instructs Th17 differentiation by bridging Dectin activation to EPHB2 signaling in innate antifungal response

“…T-cell activation Rho GTPase-activating protein (TAGAP) is a GTPase-activating protein, and many single nucleotide polymorphisms (SNPs) near or within the TAGAP gene have been found to be associated with susceptibility to many autoimmune diseases and infectious diseases, including MS, Crohn's disease, psoriasis, RA, celiac disease, and candidemia [17][18][19][20][21] . TAGAP protein is a GAP domain containing protein, and previous study found that TAGAP has a role in T-cell differentiation 22,23 . Here, we report that TAGAP is required for Dectin-1, Dectin-2/3 and mincle ligands-induced signaling pathway activation and proinflammatory induction in macrophages.…”