The role of ICAM-1 mediated T cell:T cell interactions on CD8+ T cell effector function and differentiation

Abstract

CD8+ T cells are vital components to the immune system and serve as crucial effectors in the elimination of infected cells and pathogens. During the course of an immune response many interactions occur among antigen presenting cells and T cells, as well as, eventual contacts between activated T cells and target cells. However, during the stimulation of T cells, interactions exist among T cells themselves. These adhesion molecule mediated T cell activation clusters occur both in vitro and in vivo. Here we demonstrate the role of CD8+ T cell clusters on the eventual effector function and differentiation of CD8+ T cells. Our findings reveal that T cell clusters mediated via ICAM-1:LFA-1 interactions, help to dampen the immune response by regulating expression levels of the effector markers interferon-gamma and granzyme B, as well as, cytotoxicity. Understanding the mechanisms by which this effector regulation occurs is complex. Our data suggest that unclustered T cells sense an increased amount of antigen as shown through Nur77-GFP studies. In addition, our findings demonstrate a dependence on T cell cluster formation and contact in general for the upregulation of the immune inhibitory protein CTLA-4. CTLA-4 suppresses CD8+ T cell immunity via the downregulation of the transcription factor eomesodermin and thereby regulates the production of both interferon-gamma and granzyme B. Similar effector function studies, under certain conditions, are indeed shown in vivo as well. Thus, T cell clusters regulate the tuning of CD8+ T cell function and terminal differentiation. These studies contribute to our knowledge of the necessity of T cell interactions and crosstalk during priming and potentially, via cluster manipulation, we hope to augment vaccine efficacy and anti-tumor immunotherapeutics.