T-cell receptor- and CD28-induced Vav1 activity is required for the accumulation of primed T cells into antigenic tissue

TY - JOUR

T1 - T-cell receptor- and CD28-induced Vav1 activity is required for the accumulation of primed T cells into antigenic tissue

AU - David, Rachel

AU - Ma, Liang

AU - Ivetic, Alex

AU - Takesono, Aya

AU - Ridley, Anne

AU - Chai, Jian-Guo

AU - Tybulewicz, Victor L.

AU - Marelli-Berg, Federica M.

PY - 2009/4/16

Y1 - 2009/4/16

N2 - Localization of primed T cells to antigenic tissue is essential for the development of effective immunity. Together with tissue-selective homing molecules, T-cell receptor (TCR)- and CD28-mediated signals have been shown to promote transendothelial migration of specific T cells into nonlymphoid antigen-rich tissue. However, the cellular and molecular requirements for T-cell accumulation to target tissue following their recruitment are largely undefined. The guanine nucleotide exchange factor (GEF) Vav1 has an integral role in coupling TCR and CD28 to signaling pathways that regulate T-cell activation and migration. Here, we have investigated the contribution of TCR- and CD28-induced Vav1 activity to the trafficking and localization of primed HY-specific CD4(+) T cells to antigenic sites. Severe migratory defects displayed by Vav1(-/-) T cells in vitro were fully compensated by a combination of shear flow and chemokines, leading to normal recruitment of Vav1(-/-) T cells in vivo. In contrast, Vav1(-/-) T-cell retention into antigen-rich tissue was severely impaired, reflecting T cells' inability to engage in sustained TCR- and CD28-mediated interactions with tissue-resident antigen-presenting cells (APCs). This novel function of APC-induced, and TCR- and CD28-mediated Vav1 activity in the regulation of effector T-cell immunity highlights its potential as a therapeutic target in T cell-mediated tissue damage. (Blood. 2009; 113: 3696-3705)

AB - Localization of primed T cells to antigenic tissue is essential for the development of effective immunity. Together with tissue-selective homing molecules, T-cell receptor (TCR)- and CD28-mediated signals have been shown to promote transendothelial migration of specific T cells into nonlymphoid antigen-rich tissue. However, the cellular and molecular requirements for T-cell accumulation to target tissue following their recruitment are largely undefined. The guanine nucleotide exchange factor (GEF) Vav1 has an integral role in coupling TCR and CD28 to signaling pathways that regulate T-cell activation and migration. Here, we have investigated the contribution of TCR- and CD28-induced Vav1 activity to the trafficking and localization of primed HY-specific CD4(+) T cells to antigenic sites. Severe migratory defects displayed by Vav1(-/-) T cells in vitro were fully compensated by a combination of shear flow and chemokines, leading to normal recruitment of Vav1(-/-) T cells in vivo. In contrast, Vav1(-/-) T-cell retention into antigen-rich tissue was severely impaired, reflecting T cells' inability to engage in sustained TCR- and CD28-mediated interactions with tissue-resident antigen-presenting cells (APCs). This novel function of APC-induced, and TCR- and CD28-mediated Vav1 activity in the regulation of effector T-cell immunity highlights its potential as a therapeutic target in T cell-mediated tissue damage. (Blood. 2009; 113: 3696-3705)

U2 - 10.1182/blood-2008-09-176511

DO - 10.1182/blood-2008-09-176511

M3 - Article

SN - 1528-0020

VL - 113

SP - 3696

EP - 3705

JO - Blood

JF - Blood

IS - 16

ER -