asymmetric division; adaptive immunity; memory; cell polarity; CD4+ T cell differentiation
Keck Simone, Schmaler Mathias, Ganter Stefan, Wyss Lena, Oberle Susanne, Huseby Eric S, Zehn Dietmar, King Carolyn G (2014), Antigen affinity and antigen dose exert distinct influences on CD4 T-cell differentiation., in Proceedings of the National Academy of Sciences of the United States of America
, 111(41), 14852-7.
Stepanek Ondrej, Prabhakar Arvind S, Osswald Celine, King Carolyn G, Bulek Anna, Naeher Dieter, Beaufils-Hugot Marina, Abanto Michael L, Galati Virginie, Hausmann Barbara, Lang Rosemarie, Cole David K, Huseby Eric S, Sewell Andrew K, Chakraborty Arup K, Palmer Ed (2014), Coreceptor scanning by the T cell receptor provides a mechanism for T cell tolerance., in Cell
, 159(2), 333-45.
1. SummaryAn effective immune response relies on CD4+ helper T cell activation, differentiation and development into memory T cells that contribute to protective recall responses. One way that heterogeneous T cell differentiation can be achieved is through asymmetric cell division, whereby one parent cell gives rise to two daughter cells with differential cell fates. Recent data from our laboratory have revealed asymmetric division as an important mechanistic link between TCR affinity and CD8+ effector T cell differentiation. Although asymmetric division has been reported for CD4+ T cells, the specific mechanisms and functional outcome of asymmetric division have not been described. We hypothesize that TCR affinity will have a major impact on the induction of asymmetric division, priming of CD4+ T cell responses and shaping of the memory CD4+ T cell compartment. Results from the experiments proposed herein will provide valuable new insight into the cellular and molecular mechanisms controlling adaptive immunity. The grant has 3 aims. Aim 1: Dissect the role of TCR affinity in CD4+ T cell differentiationThere is a strong link between the strength of stimulation and extent of T cell differentiation. How TCR affinity regulates the acquisition of diverse CD4+ T cell fates is not well understood. Recent reports indicate that differentiation into follicular helper CD4+ T cells and central memory CD4+ T cells may involve a common developmental pathway that is dependent on dampening of IL-2Ra mediated signals. Although low affinity ligands typically induce lower levels of IL-2Ra, whether or not these ligands support heterogeneous CD4+ T cell differentiation is not known. The experiments outlined in this aim will examine the development and functional capacities of follicular helper and CD4+ memory T cells following infection with Listeria expressing high affinity or altered peptide ligands for TCR.Aim 2: Investigate the contribution of asymmetric division to CD4+ T cell differentiationOur previous experiments revealed an antigen affinity threshold for the induction of asymmetric division and fate specification in CD8+ T cells. Preliminary experiments with TCR transgenic CD4+ T cells responding to Listeria infection indicate that IL-2Ra and Tbet are asymmetrically distributed in a large proportion of dividing cells. IL-2Ra signals appear to play a role in promoting CD4+ effector T cell differentiation and conversely, suppressing follicular helper T cell and central memory T cell differentiation. The experiments described in this aim intend to elucidate the role of asymmetric division as a molecular mechanism for CD4+ T cell differentiation and to assess the functional outcome of asymmetrically divided daughter T cells. In addition, we will examine the localization and activation of transcription factors and proteins with a conserved role in stem cell renewal and CD4+ T cell differentiation to identify additional pathways involved in CD4+ T cell asymmetric division.Aim 3: Evaluate the role of regulatory T cells in asymmetric divisionAlthough most self-reactive T cells are eliminated during negative selection in the thymus, a small number of self-reactive T cells escape selection and persist in the periphery. Regulatory T cells (Tregs) have been shown to dominantly suppress the activation of these T cells thereby acting as a critical component of peripheral tolerance. The mechanisms by which Tregs inhibit effector responses are not completely understood. We hypothesize that Treg mediated inhibition of stable effector T cell contacts with antigen presenting cells will prevent T cell polarization, resulting in symmetric, “non dangerous” division. The experiments described in this aim are designed to test the efficacy of Treg suppression on high versus low affinity T cell responses and to determine whether Treg ablation in vivo promotes asymmetric division and enhances T cell responses to lower affinity antigens.