Bernard Malissen
Bernard Malissen
affiliation: Centre d'Immunologie de Marseille-­Luminy, France
research area(s): Developmental Biology, Molecular Biology
Course: Basic and Applied Immunology
University/Istitution: Università Vita-Salute San Raffaele
The work of Bernard Malissen focuses on T lymphocytes. These cells circulate throughout the body and scan the surface of antigen-presenting cells for the presence of minute amounts of foreign peptides bound to major histocompatibility complex (MHC) molecules. To carry out this task, they use a specific receptor, the T cell antigen receptor (TCR), that turns on a wide spectrum of cellular responses that are at the basis of adaptive immunity. The genes coding for TCR are formed by stochastic somatic DNA recombinations. Due to this unique attribute, developing T cells assemble sophisticated molecular sensors that allow them to counterbalance the stochastic nature of TCR gene rearrangements, and to avoid autoimmune disorders. During the past twenty years, the primary objective of the team of Bernard Malissen has been to decipher the molecular basis of T cell recognition events and of their ensuing conversion into intracellular signals.

To reduce the complexity of the lymphocyte populations that constitute the adaptive immune system, Bernard Malissen developed in 1978 one of the first method allowing the in vitro propagation of functional human T cell clones. This approach permitted the characterization of molecules associated with T cell recognition events. However, it was already clear at that time that T cell activation events involve the concerted interplay of many molecular species, and that more powerful approaches were needed to dissect the molecular cascade linking TCR occupancy to the generation of early T cell activation events. To reach this aim, he joined the laboratory of Leroy Hood (Caltech, USA) in 1982, and developed gene transfer techniques permitting the sequential expression of several genes within a given cell recipient. He specifically showed that transfer of MHC class II genes alone confers on fibroblastic cells the capacity to present antigen to T cells. These findings facilitated further dissection of the structure-function relationships existing between MHC molecules, antigenic peptides, and TCRs.

After establishing in 1984 a research team in the frame of the Centre d'Immunologie INSERM-CNRS de Marseille-Luminy (France), he demonstrated that the transfer of TCR and CD8 molecule is necessary and sufficient to confer to a “naïve” T cell the ability to recognize a specific peptide/MHC class I complex. The possibility to reprogram a T cell with 5 different genes allowed him to establish the concept of CD3 "signaling modules". Based on the exon-intron organization of the transduction motifs found in the cytoplasmic tail of most of the polypeptides associated with antigen receptors or Fc receptors, he showed that the present-day transduction motifs stem from on a common primordial building block made of two exons.In parallel studies, conducted in collaboration with Marie Malissen, he provided the first direct evidence for the existence of chromosomal inversion during TCR gene rearrangements.

During the last ten years, the laboratory of Bernard and Marie Malissen developed mice harboring specific deletion and/or modification in genes coding for components of TCR transduction cassette, and worked out the organization of the pre-TCR, a key molecular sensor used by developing T cells to control the outcome of early TCR gene rearrangements. Analysis of an allelic series involving the LAT adaptor, a key “hub” of the TCR signalling cassette, revealed that there exists a pathology proper to defective LAT signalosomes. This pathology is characterized by a lymphoproliferative disorder involving polyclonal Th2 effectors that belong to the alpha/beta or gamma/delta T cell lineage, and results in fulminant hypergammaglobulinemia E and G1. This pathological condition, emphasizes that the LAT adaptor constitutes a key signalling node controlling T cell homesostasis and terminal differentiation.

The long term interests of Bernard Malissen in the molecular biology of T cells also formed the basis for the development of diagnostic tools allowing to track T cells in various immunopathologies. He recently developed a new line of research aimed at tackling the dynamics and function of dendritic cells in vivo. Using appropriate knockin mice, his laboratory specifically focused on Langerhans cells, a dendritic cell subset that resides in their immature state in epidermis and mucosal epithelia.

Finally, Bernard Malissen has been for 11 years (1994-2005), the head of the Centre d’Immunologie de Marseille-Luminy, a joint unit of the French public research agencies CNRS and INSERM that host close to 100 scientists. He also participates to several Editorial Boards (Immunity, Journal of Experimental Medicine, EMBO Journal…). He was elected as a Honorary Member of the American Association of immunologists when he was 43 years old and as a Member of the French Academy of Science in 2003.
T lymphocytes scan the surface of dendritic cells for the presence of foreign antigenic peptides bound to major histocompatibility complex (MHC) molecules. To carry out this daunting task, they use a receptor known as the T cell antigen receptor. The primary objective of our team is to elucidate the molecular basis of T cell antigen recognition and of its ensuing conversion into intracellular signals that are at the basis of adaptive immune responses. We also pursued studies aiming at disentangling the complexity of the dendritic cell networks that are present in lymphoid and nonlymphoid tissues.
Our laboratory studies T lymphocytes and dendritic cells (DCs) since they are at the basis of adaptive immunity. In the case of T cells, we pursue the genetic dissection of the architecture of the signaling cassette operated by the T cell receptor (TCR). We showed that partial-loss-of-function mutations affecting the gene coding for the LAT adaptor result in stereotyped and devastating lymphoproliferative disorders with excessive production of T helper type 2 (Th2) cytokines. The extreme vulnerability of LAT likely results from the fact that it constitutes a highly connected signaling hub of the TCR signaling cassette exerting both positive and negative regulatory functions that are mandatory for proper T cell homeostasy.Our objective is to elucidate the mechanisms through which during physiological, antigen-driven T cell responses LAT leads first to activation of intracellular effectors involved in cell metabolism, cell division, cell motility, cell survival and differentiation into effectors T cells and then exerts with a temporal delay a feedback inhibition that leads to rapid attenuation of the TCR signaling pathway.

Our studies have a multidisciplinary character and rely on several approaches involving the development of novel mouse models, the identification of modifier genes via ENU mutagenesis and proteomic studies of the LAT signalosome.
Based on our ongoing studies, it appears that certain pathological conditions collectively called « autoimmune » on the basis of the presence of autoantibodies do not result from the presence of self-reactive T cells – as generally thought - but from defect in the cell-intrinsic mechanisms that normally keep in check physiologic T cell responses.
In parallel, we have pursued studies aiming at disentangling the complexity of the DC networks that are present in lymphoid and non-lymphoid tissues. We will take advantage of our ability to identify homogeneous DC subsets to develop comparative transcriptomic analysis with the team of M. Dalod. Such approach is expected to provide hints on the functional specialization of those various DC subsets and to identify genes that can be subsequently manipulated to develop mice allowing the ablation of such subsets in vivo.

Integrated T-cell receptor and costimulatory signals determine TGF-β-dependent differentiation and maintenance of Foxp3(+) regulatory T cells
Gabryšová L., Christensen JR., Wu X., Kissenpfennig A., Malissen B., O'Garra A., Eur J Immunol., 2011, 1242-1248, 41(5)
Contrasting roles of macrophages and dendritic cells in controlling initial pulmonary Brucella infection
Archambaud, C., Salcedo, S. P., Lelouard, H., Devilard, E., de Bovis, B., Van Rooijen, N., Gorvel, J. P., Malissen, B., Eur J Immunol, 2010, 3458-71, 40, PMID: 21108467
Egocentric pre-T-cell receptors
Malissen, B., Luche, H., Nature, 2010, 793-4, 467, PMID: 20944732
From skin dendritic cells to a simplified classification of human and mouse dendritic cell subsets
LAT signaling pathology: an "autoimmune" condition without T cell self-reactivity
Roncagalli, R., Mingueneau, M., Gregoire, C., Malissen, M., Malissen, B., Trends Immunol, 2010, 253-9, 31, PMID: 20542732
The T helper type 2 response to cysteine proteases requires dendritic cell-basophil cooperation via ROS-mediated signaling
Tang, H., Cao, W., Kasturi, S. P., Ravindran, R., Nakaya, H. I., Kundu, K., Murthy, N., Kepler, T. B., Malissen, B., Pulendran, B., Nat Immunol, 2010, 608-17, 11, PMID: 20495560
Comparative genomics as a tool to reveal functional equivalences between human and mouse dendritic cell subsets
Crozat, K., Guiton, R., Guilliams, M., Henri, S., Baranek, T., Schwartz-Cornil, I., Malissen, B., Dalod, M., Immunol Rev, 2010, 177-98, 234, PMID: 20193019
Tonic ubiquitylation controls T-cell receptor:CD3 complex expression during T-cell development
Wang, H., Holst, J., Woo, S. R., Guy, C., Bettini, M., Wang, Y., Shafer, A., Naramura, M., Mingueneau, M., Dragone, L. L., Hayes, S. M., Malissen, B., Band, H., Vignali, D. A., EMBO J, 2010, 1285-98, 29, PMID: 20150895
Foxp3+ T cells induce perforin-dependent dendritic cell death in tumor-draining lymph nodes
Boissonnas, A., Scholer-Dahirel, A., Simon-Blancal, V., Pace, L., Valet, F., Kissenpfennig, A., Sparwasser, T., Malissen, B., Fetler, L., Amigorena, S., Immunity, 2010, 266-78, 32, PMID: 20137985
Skin-draining lymph nodes contain dermis-derived CD103(-) dendritic cells that constitutively produce retinoic acid and induce Foxp3(+) regulatory T cells
Guilliams, M., Crozat, K., Henri, S., Tamoutounour, S., Grenot, P., Devilard, E., de Bovis, B., Alexopoulou, L., Dalod, M., Malissen, B., Blood, 2010, 1958-68, 115, PMID: 20068222
CD207+ CD103+ dermal dendritic cells cross-present keratinocyte-derived antigens irrespective of the presence of Langerhans cells
Henri, S., Poulin, L. F., Tamoutounour, S., Ardouin, L., Guilliams, M., de Bovis, B., Devilard, E., Viret, C., Azukizawa, H., Kissenpfennig, A., Malissen, B., J Exp Med, 2009, 189-206, 207, PMID: 20038600
Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic effectors that function independently of the T cell receptor
Mingueneau, M., Roncagalli, R., Gregoire, C., Kissenpfennig, A., Miazek, A., Archambaud, C., Wang, Y., Perrin, P., Bertosio, E., Sansoni, A., Richelme, S., Locksley, R. M., Aguado, E., Malissen, M., Malissen, B., Immunity, 2009, 197-208, 31
Thymus-specific serine protease regulates positive selection of a subset of CD4+ thymocytes
Gommeaux, J., Gregoire, C., Nguessan, P., Richelme, M., Malissen, M., Guerder, S., Malissen, B., Carrier, A., Eur J Immunol, 2009, 956-64, 39
STAT6 deletion converts the Th2 inflammatory pathology afflicting Lat(Y136F) mice into a lymphoproliferative disorder involving Th1 and CD8 effector T cells
Archambaud, C., Sansoni, A., Mingueneau, M., Devilard, E., Delsol, G., Malissen, B., Malissen, M., J Immunol, 2009, 2680-9, 182, PMID: 19234162
Role of beta7 integrin and the chemokine/chemokine receptor pair CCL25/CCR9 in modeled TNF-dependent Crohn's disease
Apostolaki, M., Manoloukos, M., Roulis, M., Wurbel, M. A., Muller, W., Papadakis, K. A., Kontoyiannis, D. L., Malissen, B., Kollias, G., Gastroenterology, 2008, 2025-35, 134
The proline-rich sequence of CD3epsilon controls T cell antigen receptor expression on and signaling potency in preselection CD4+CD8+ thymocytes
Mingueneau, M., Sansoni, A., Gregoire, C., Roncagalli, R., Aguado, E., Weiss, A., Malissen, M., Malissen, B., Nat Immunol, 2008, 522-32, 9
Th2 lymphoproliferative disorder of LatY136F mutant mice unfolds independently of TCR-MHC engagement and is insensitive to the action of Foxp3+ regulatory T cells
Wang, Y., Kissenpfennig, A., Mingueneau, M., Richelme, S., Perrin, P., Chevrier, S., Genton, C., Lucas, B., DiSanto, J. P., Acha-Orbea, H., Malissen, B., Malissen, M., J Immunol, 2008, 1565-75, 180
The dermis contains langerin+ dendritic cells that develop and function independently of epidermal Langerhans cells
Poulin, L. F., Henri, S., de Bovis, B., Devilard, E., Kissenpfennig, A., Malissen, B., J Exp Med, 2007, 3119-31, 204
Project Title:
Dissecting the function of skin dendritic cell subsets
Over the last five years, our group has largely contributed to decipher the complexity of the skin DC network. We have created innovative mouse models allowing to disentangle the skin DC complexity and to unravel the functions of some specific skin DC subsets.The present proposal capitalizes on our ability to perform a comprehensive analysis of the phenotype of the skin DCs and aims at:

- Constructing innovative mouse models to further unravel the functional complexity of the network of DCs found in the skin, especially the role of retinoic acid (RA) production during the induction of T reg cells in vivo.
- Understanding the mechanisms of cross-presentation and cross-tolerance induced by the CD207+ CD103+ DDCs that reside in the dermis.
- Providing transcriptomic signature of each of the homogeneous skin DC subsets we have been able to identify.
- Imaging by confocal and intravital microscopy the CD207+ CD103+ DDC subset and its antigen-specific interactions with CD8+ T cells.