Control of human T helper cell differentiation

Functionally distinct subsets of CD4⁺ T cells are essential for efficient immune responses against different types of pathogens. T helper type 1 (Th1) cells promote cell-mediated immunity to combat intracellular pathogens. Uncontrolled Th1 responses are associated with autoimmune diseases, indicating that Th1 development must be tightly controlled.

We have studied the mechanisms that control differentiation of naive CD4⁺ T cells into Th1 cells. In particular, we have analyzed how signals originating at the TCR and at cytokine receptors are integrated to shape a Th1-specific gene expression program. We found that TCR signaling induces rapid recruitment of the BAF chromatin remodeling complex and H3 acetylation at the IL-12Rβ2 regulatory regions. We show a synergistic effect of TCR-induced chromatin remodeling and IL-12-induced STAT4 activation to direct IL-12Rβ2 expression during human Th1 cell development. In contrast to IL-12Rβ2, TCR-induced T-bet expression and remodeling of the T-bet locus are inhibited by cyclosporine A. Our results indicate that two independent signaling pathways act in parallel to control human Th1 cell differentiation.

A systems biology approach to study human CD4⁺ T lymphocyte subsets

The construction of robust molecular fingerprints for physiologic and pathologic cellular phenotypes is of great value for the understanding of cellular pathophysiology and has direct applications in the biomedical domain. In collaboration with A. Benecke (IHES, Bures-sur-Yvette) we have devised a novel strategy combining gene expression profiling and global signaling pathway analysis by aid of a geometric correction to generate unique transcriptome signatures. Our integrated global pathway analysis has revealed new important features of human regulatory T cells.

A Novel Regulator of Ubiquitination Processes: the COP9 Signalosome (CSN)

Ubiquitin-mediated proteolysis plays an important role in many fundamental cellular processes, including cell cycle regulation, differentiation, and gene transcription. Alterations in this pathway contribute to the pathogenesis of several diseases, among which malignancies and immunopathologies. The CSN has been recently identified as a regulator of ubiquitination processes. CSN pleiotropic function may be related to its ability to regulate the activity of cullin-RING ubiquitin ligases, such as the SCF complex. However, the mechanisms and the targets of CSN activity in mammalian cells are still debated. This project investigates the biochemical and molecular functions of the human CSN and its role in regulating ubiquitination processes that control cell proliferation and gene expression. We have used lentivirus-mediated RNA interference to target the expression of CSN subunits. Our data indicate that the CSN is necessary for the stabilization of SCF components and for the assembly of a functional SCF^Skp2 complex, and is therefore essential for cell cycle progression of human cells.