Antigen presentation and T cell activation

Research Interests

Adaptive immunity begins with the generation of effector T cells from their naïve precursors, upon interaction with professional Antigen Presenting Cells (APC). Once generated, effector T cells are the central actors of antigen-specific immune responses and their function is strongly influenced by the environment where leukocytes interact. Signaling through Pattern Recognition Receptors (PRR) is known to influence T cell responses, with both beneficial and detrimental consequences.
While the instructive role of PRR in cell fate decisions of naïve T lymphocytes has been largely investigated, a careful analysis of how PRR agonists modulate effector T cell function is still missing. This aspect is of crucial importance for the development of human vaccines, since one would like to enhance effector T cell activity, without causing autoimmunity.
We are studying how PRR signaling modulates the activation of human effector T cells in the presence of different APC. Our specific goals are to: i) dissect the capacity of non-professional APC to expand functionally different effector T cells in the presence of PRR agonists; ii) study the biological outcome of the interaction between effector T cells with different types of APC; iii) characterize the molecular dynamics occurring at the interface between effector T cells and APC.

We seek creative and highly motivated PhD students. Interested candidates should send their CV, a letter of motivation, and contact information of 2-3 references to Elisabetta Padovan.

Group Members

Research Project

How Pattern Recognition Receptors signaling controls T lymphocytes activation

Classically, CD4+ T cell responses result from the triggering of their T cell receptor (TCR) by MHC-II-peptide complexes expressed on APC, and the outcome of this process is influenced by the engagement of PRR. During activation, a CD4+ T cell can receive a PRR signal indirectly (in trans) or directly (in cis). Activation in trans is provided by soluble and cell-bound factors expressed by APC that have been stimulated through their PRR. Trans-activating signals induce naïve T cell proliferation and differentiation into cytokine-producing T helper cells. However, T cells activated through the TCR complex also express functional PRR and respond to PRR agonists with increased proliferation and cytokines secretion. Whether PRR activation in cis occurs during APC/T cell interactions and how T cells integrate trans- and cis-activating signals into their physiology remains poorly understood. We are currently addressing these issues by employing polarized human T cell clones producing IFN- (Th1) and/or IL-17 (Th17) reactive to bacterial enterotoxins. Our aim is to define possible differences in the capacity of these polarized effector T cells to communicate with APC, in the presence or absence of PRR stimuli.

Funding

Fundação para Ciencia e a Tecnologia (FCT) Project Grant, Portugal

Collaborators

Instituto Gulbenkian de Ciência
Jocelyne Demengeot
Iris Caramalho

Max Planck Institute for Immunebiology, Freiburg, D
Markus Simon

Research Project

Adjuvanticity of microbial-derived particles and synthetic analogs in vitro

Engagement of Toll-Like Receptors (TLR) on APC by conserved molecules expressed by natural pathogens or live/attenuated vaccines is crucial for the development of long-term immuneprotection. Conversely, antigen formulations that lack the capacity to signal through TLR are poorly immunogenic. These observations have generated a strong demand for the rational design of synthetic analogs of TLR agonists suitable for complementing the activity of subunit vaccines. As new compounds become available, there is need to develop high throughput screening methods that can accurately predict adjuvanticity and safety of these molecules. We performed a systematic study that provides the rationale for the screening and subsequent development of adjuvants suitable for use in human vaccines based on responses observed on human T cells and APC. Our results will help to refine current methods for adjuvant selection that are based on in vivo studies using a variety of animal models not necessarily representative of human reactivity.

Funding

3R Research Foundation Switzerland Project Grant, Switzerland

Collaborators

Department of Research, University Hospital, Basel, CH
Gennaro De Libero
Regine Landmann

Max Planck Institute for Immunebiology, Freiburg, D
Markus Simon
Marina Freudenberg

Instituto Gulbenkian de Ciência
Jorge Carneiro

Publications

Carneiro J, Duarte L, Padovan, E. (2009). Limiting dilution analysis of antigen-specific T cells Methods Mol Biol 514 :95-105

Caramalho I, Faroudi M, Padovan, E, Müller S, Valitutti S. (2008). Visualizing CTL/melanoma cell interactions: multiple hits must be delivered for tumor cell annihilation. J Cell Mol Med in press

Kamgang RK, Ramos I, Rodrigues-Duarte L, Ghielmetti M, Freudenberg M, Dahinden C and Padovan, E. (2008). Using distinct molecular signatures of human monocytes and dendritic cells to predict adjuvant activity and pyrogenicity of TLR agonists Med Microbiol Immunol 197 :369-79

Padovan, E, Landmann RM and De Libero G. (2007). How pattern recognition receptor triggering influences T cell responses: a new look into the system. Trends Immunol 28 :308-314

Padovan, E. (2007). Adjuvanticity of microbial-derived particles and synthetic analogs in vitro Altex 24 :96-97

Ghielmetti M, Zwicker M, Ghielmetti T, Simon MM, Villiger PM and Padovan, E. (2005). Synthetic bacterial lipopeptide analogs facilitate naive CD4+ T cell differentiation and enhance antigen-specific HLA-II restricted responses. Eur J Immunol 35 :2434-2442

Reschner A, Moretta A, Landmann R, Heberer M, Spagnoli GC and Padovan, E. (2003). The ester-bonded palmitoyl side chains of Pam3CysSerLys4 lipopeptide account for its powerful adjuvanticity to HLA class I-restricted CD8+ T lymphocytes. Eur J Immunol 33 :2044-2052