CD40L at the interface of the innate and adaptive immune responses

Friday, November 08, 2013 — Poster Session III
10:00 a.m. – 12:00 p.m.	FAES Academic Center (Upper-Level Terrace)	FDA/CBER	MICROBIO-2

Authors

N.D. Bushar
J.A. Ragheb
E.M. Gertz
A. Schaffer

Abstract

CD40 ligand (CD40L) is a well-recognized costimulatory molecule expressed on activated CD4 T cells, which plays an indispensible role in the adaptive immune response. CD40L-CD40 interactions are critical for promoting B cell responses and CD40L deficiency underlies the X-linked form of the Hyper-IgM syndrome. Here, we demonstrate for the first time that proteins expressed by endothelial cells and fibroblasts directly costimulate the expression of CD40L on CD4 T cells through engagement of the T cell integrin receptor α4β1. Additionally, we reveal that proteins of the extracellular matrix (ECM), fibronectin and laminin can similarly costimulate CD4 T expression of CD40L through engagement of α5β1 and α6β1, respectively. Importantly, we also show that increased concentrations of VCAM1 or ECM proteins have an inhibitory effect on T cell costimulation of CD40L, suggesting that exposure to these costimulatory ligands be self-limiting and providing a mechanism for regulation of the immune response in these areas. Given the critical role for CD40-CD40L interactions during the early innate immune responses, our findings have critical implications in our understanding of early inflammatory responses, the initiation of adaptive responses, and the functional healing process.