Project

Back to overview

The role of TCR affinity in CD4+ T cell asymmetric division and differentiation

Applicant King Carolyn
Number 142645
Funding scheme Ambizione
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.01.2013 - 31.12.2015
Approved amount 398'388.00
Show all

Keywords (5)

asymmetric division; adaptive immunity; memory; cell polarity; CD4+ T cell differentiation

Lay Summary (English)

Lead
Lay summary

CD4+ T cells are critical regulators of health and disease.  Defects in T cell function can result in a variety of immune disorders including susceptibility to infectious pathogens and the development of autoimmunity.  In addition, T cell modulation of B cell responses is indispensable for establishing protective memory responses.  T cell receptor (TCR) recognition of peptide-MHC (pMHC) is an essential first step in the induction of an immune response.  Recent work has demonstrated a role for the strength of TCR interactions with pMHC in the induction of asymmetric cell division, whereby one parent cell gives rise to two daughter cells with differential cell fates.  In this project we will study the contribution of TCR affinity to heterogeneous CD4+ T cell differentiation following either infection or immunization.  We will focus on understanding the specific mechanisms and functional outcome of asymmetric division in CD4+ T cells.  Defining the rules of CD4+ T cell differentiation may provide a rational basis for the design of safe and effective vaccines.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Antigen affinity and antigen dose exert distinct influences on 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.
Coreceptor scanning by the T cell receptor provides a mechanism for T cell tolerance.
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.

Collaboration

Group / person Country
Types of collaboration
Dietmar Zehn, Swiss Vaccine Research Institute Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Timm Schroeder Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Lymphocyte Signaling Poster Generation of follicular helper and memory T cells in response to very low affinity antigen 17.05.2014 Bertinoro, Italy King Carolyn;
British Society of Immunology Talk given at a conference TCR signal strength and differentiation 02.12.2013 Liverpool, Great Britain and Northern Ireland King Carolyn;
Regulatory T cell meeting Talk given at a conference TCR affinity and CD4+ T cell differentiation 27.09.2013 Basel, Switzerland King Carolyn;
T follicular helper cells (Gordon Research Conference) Poster Generation of follicular helper cell and memory T cells in response to very low affinity antigen 20.07.2013 China, Hongkong King Carolyn;


Awards

Title Year
Forschungsfonds-Universität Basel 2014
Novartis Stiftung fuer Medizinisch-Biologische Forschung 2014
Swiss Transplantation Society Award 2013

Associated projects

Number Title Start Funding scheme
157520 Mechanisms of CD4+ T cell heterogeneity: how do T cells decide? 01.01.2016 SNSF Professorships

Abstract

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.
-