Team 11 – Fazilleau / Guerder - Institut Toulousain des Maladies Infectieuses et Inflammatoires

Antigen Presenting Cells in T cell responses

Coordinators : N. Fazilleau / S. Guerder

Scientific objectives

Antigen presenting cells, whether dendritic cells (DC), B cells or monocytes are critical regulators of immune responses. Hence, the functional program of the antigen-presenting will determine whether T cell tolerance or protective immunity is induced. The main focus of our team are to determine how the function of DC are program during ontogeny and to examine how these cellular interactions between different antigen-presenting cells and T cells impact immune responses in physiological or pathological contexts. We thus examine the mechanisms that regulate DC function to either induce T cell tolerance in autoimmune context or appropriate immune response for vaccine development or for the development of antitumor responses. We also examine how antigen-presenting cell-derived factors may contribute to the development of effector and memory T cells with a particular focus on the regulators of B cell immunity, T Follicular Helper cells (Tfh) and T Follicular regulatory cells (Tfr).

Our Projects

AXIS 1: Dendritic cells in central tolerance and autoimmunity

DC are major contributors to T cell tolerance.

In the thymus, the different DC subsets constitutively process and present peptides derived from self-proteins to developing thymocytes to induce either deletion of the self-reactive thymocytes or regulatory T cell development. Our team has uncovered the unique properties of the thymus specific serine protease (TSSP) in editing the “self” peptide repertoire presented by stromal cells in the thymus and its impact on the development of the auto-reactive T cell repertoire. Hence we showed that lack of TSSP expression by thymic DC enhances deletion of self-reactive CD4 T cells and thus prevents type 1 diabetes or reduces the severity of experimental autoimmune encephalomyelitis. In continuation, we further characterize TSSP function and assess new strategies based on the unique properties of TSSP for the treatment of these T cell-mediated autoimmune diseases.
Finally, by combining genome wide studies and functional studies we examine how the thymic environment condition thymic DC differentiation and maturation and endowed the thymic DC with constitutive antigen presenting function.

AXIS 2: Physiology, anatomy and regulation of T-dependent B cell responses

The aim of vaccination is to generate memory cells endowed with enhanced or novel functional capacities capable of inducing an amplified and faster immune response to subsequent pathogen exposure. We postulate that fitness and quality of the humoral immunity conferred during an immune response rely on the manipulation of Dendritic cells (DC) that regulate Tfh and Tfr development, consequently germinal center (GC) reactions and, ultimately, the composition of the memory Tfh and B compartments.

Figpart2-1 Using specific antigen models that we have developed in the lab, our objectives are to evaluate: 1- the nature of the delivery system and the nature of the immunomodulatory signals that control these events, 2- the links between the anatomy of the memory compartments and memory fitness, 3- the influence of vaccine formulation on Ag availability and persistence, 4- the crosstalk between different memory cells that tightly collaborate during recall responses.

On one hand, we are assessing the impact of TLR and STING agonists alone or in combination in different delivery forms: lipidated, alum adsorbed, nanoparticles on the antigen-specific response and its protective effect to bacterial infection. On a second hand, our goal is also to circumvent vaccine hyporesponsiveness at extreme ages (neonatal and elderly). We plan on optimizing adjuvant formulation strategies that drive human Tfh cell differentiation.

One other aspect of our studies focuses on how Foxp3+ T cells regulate humoral responses. The output of the GC varies with the inflammatory context. Until now, such differences were attributed to the Tfh heterogeneity. However, we recently showed that T cell priming by DC also impacts the Tfr compartment, demonstrating that Tfr share many proprieties with Tfh such as antigen-specificity, polarization according to the inflammatory milieu and promotion of GC reaction. This suggests that the multifaceted function of Tfr may reflect the function of different cell subsets. In this context, we are deciphering the heterogeneity of the Tfr compartment and evaluating the physiological role of the different Tfr subsets in response to non-self antigen or during B cell-dependent encephalomyelitis.

Finally, it is now clear that the Tfh/B crosstalk controls reciprocally Tfh and B-cell plasticity. As such we demonstrated that BCR affinity conrols effector Tfh development. We also revealed that the memory maintenance and function after antigen re-encounter rely both on Tfh/B cognate interactions.

figpart2-2 We now describe in depth memory Tfh cells and evaluate the physiological impact of these cell interactions on the quality and longevity of a humoral response in mouse and human settings. Moreover, we also study human autoimmune pathologies mediated by auto-antibodies such as Pemphigus vulgaris and assess how the response of patients to B-cell depleting treatment relies not only on the inhibition of the auto-reactive B cells but also on their cognate cell regulators, namely the Tfh cells.

AXIS 3: Development of anti-tumor T cell responses

On one hand, we explore how the molecular interactions during the B-Tfh crosstalk participate to lymphomagenesis in the context of follicular and angio-immunoblastic lymphoma in order to discover new therapeutic targets.

On the other hand, we assess the mechanisms promoting or inhibiting DC recruitment and function within tumors. We recently showed that the site of tumor development determine tumor immunogenicity which relates to the kinetic of antigen-laden DC recruitment in draining lymph nodes. We now characterize the route and impact of the tumor environment on DC recruitment within tumors and define the molecular mechanisms involved using established live 2-photon imaging of tumor explants. Our long-term objective is to determine whether the factors that improve DC recruitment within tumors also promote DC recruitment in draining lymph nodes and, consequently, protective T cell response. In parallel, by combining genomic and functional studies, we study how the tumor environment modifies the function of DCs in tumors in order to identify factors allowing to reprogram them and to induce protective antitumor responses.

Other informations

Members

Publications

2021

Baumjohann, D; Fazilleau, N

Antigen-dependent multistep differentiation of T follicular helper cells and its role in SARS-CoV-2 infection and vaccination. Journal Article

Eur J Immunol., 2021.

Antigen Presenting Cells in T cell responses

Scientific objectives

Our Projects

AXIS 1: Dendritic cells in central tolerance and autoimmunity

DC are major contributors to T cell tolerance.

AXIS 2: Physiology, anatomy and regulation of T-dependent B cell responses

AXIS 3: Development of anti-tumor T cell responses

On one hand, we explore how the molecular interactions during the B-Tfh crosstalk participate to lymphomagenesis in the context of follicular and angio-immunoblastic lymphoma in order to discover new therapeutic targets.

Other informations

Members

Publications

2021

2020

2019

2018

2017

2016

2015

2014

2013

2012

2011

Impact on the society

Alumni

Collaborations

ANRS

EFSD

Fondation de recherche médicale

Institut National Du Cancer

JDFR

Les actions marie sklodowska curie

INSERM

CNRS

ARSEP

Fondation de recherche médicale

Ligue contre le cancer

Fondation ARC

Seventh Framework Programme

Région Occitanie

Société Française de Dermatologie

Université Paul Sabatier