When mobile T cells encounter an ARC, initial TCR signaling activates LFA-1, leading the formation of a stable T cell:APC conjugate. The stability of this conjugate contributes to the sustained T cell signaling that is required for T cell proliferation and the generation of effector cells. When the formation of stable T cell:APC conjugates is disrupted, T cells can still proliferate, suggesting that T cells can temporally integrate signals derived from multiple transient interactions with ARC. Interestingly, these alterations in the kinetics of T cell:APC interactions correlate with a change in T cell differentiation, leading to the induction of tolerance or a shift in the balance of Th1/Th2 effector cell populations. We have found that in addition to its important role in T cell adhesion, LFA-1 can modulate the organization of proteins within the immunological synapse that forms at the T cell:APC interface. Our preliminary data suggest that the ability of LFA-1 to direct the organization of the synapse can modulate proximal signaling events. In contrast, we propose that the ability of LFA-1 to regulate Th cell differentiation may be mediated primarily by adhesion and the kinetics of T cell:APC interactions. The overall goal of this application is to directly test how these independent functions of LFA-1 contribute to the magnitude and kinetics of T cell activation and directs subsequent T cell differentiation in vitro and in vivo. This will be accomplished through four Aims: (1) Determine how LFA enhances class II localization to the cSMAC; (2) Determine the molecular basis and functional impact of LFA-1-mediated exclusion of CD45 from the immunological synapse; (3) Identify the molecular targets for LFA-1-mediated down regulation of Th2 responses; and (4) Determine how LFA-1-mediated changes in the dynamics of T cell:APC interactions impacts on the generation of CD4 effector cells. LFA-1 antagonists have been used successfully to block many detrimental immune responses, but the relative efficacy of these reagents in inhibiting initial T cell activation, inducing tolerance, modulating effector cell differentiation, or restricting homing of activated cells to inflammatory sites is not clear. Our studies will help unravel the multiple mechanisms that might contribute to the clinically significant immunomodulatory capacity of LFA-1 antagonists. Ultimately, understanding the factors that determine the nature of T cell immune response are key to the development of potent and specific immune modulators. ? ? ?
|Cook, Kevin D; Miller, Jim (2010) TCR-dependent translational control of GATA-3 enhances Th2 differentiation. J Immunol 185:3209-16|
|Graf, Beth; Bushnell, Timothy; Miller, Jim (2007) LFA-1-mediated T cell costimulation through increased localization of TCR/class II complexes to the central supramolecular activation cluster and exclusion of CD45 from the immunological synapse. J Immunol 179:1616-24|
|Sanchez-Lockhart, Mariano; Miller, Jim (2006) Engagement of CD28 outside of the immunological synapse results in up-regulation of IL-2 mRNA stability but not IL-2 transcription. J Immunol 176:4778-84|
|Jenks, Scott A; Eisfelder, Bartholomew J; Miller, Jim (2005) LFA-1 co-stimulation inhibits T(h)2 differentiation by down-modulating IL-4 responsiveness. Int Immunol 17:315-23|
|Sanchez-Lockhart, Mariano; Marin, Elides; Graf, Beth et al. (2004) Cutting edge: CD28-mediated transcriptional and posttranscriptional regulation of IL-2 expression are controlled through different signaling pathways. J Immunol 173:7120-4|
|Abraham, C; Miller, J (2001) Molecular mechanisms of IL-2 gene regulation following costimulation through LFA-1. J Immunol 167:5193-201|