Regulation of integrin LFA-1 (CD11a/CD18) during T cell migration and activation (CAM1P.227)

Abstract

Abstract T cell entry into a lymph node is dependent upon several events, including activation of chemokine receptor CCR7 and adhesion of integrin LFA1. T cells become highly motile to scan dendritic cells (DCs) for cognate antigen (Ag), utilizing active LFA1 at the leading edge. Ag challenge induces stable T-DC interactions and immunological synapse (IS) formation, where active LFA1 relocates. LFA1 is an adhesive force in migration and IS formation, but the outcome of chemokine and T cell receptor (TCR) signals are different, as the former induce “go” and the latter mediate “stop” signals. We hypothesize the magnitude of chemokine and TCR signals will determine the outcome of LFA1 mediated interactions and thus T cell activation. We generated fluorescent knock-in (KI) mice to visualize LFA1 distribution and activation patterns. We mated these KI mice with OTI TCR transgenic mice to study LFA1 distribution in T cells activated by varying TCR signal strength with altered peptide ligands (APL). We have thus far shown LFA-1 clusters faster and remains clustered longer at the contact site in interactions with cognate Ag compared to those with weaker APLs. We are repeating these experiments in our LFA1 FRET mice, which allow us to visualize the LFA1 activation, to determine if LFA1 activation induces the LFA1 clustering seen in interactions with cognate Ag. We have also incorporated a photoactivatable chemokine receptor, PA-CCR7, to assess the effect of chemokine signal strength on LFA1.