Our lab studies the molecular mechanisms that control the differentiation and function of human helper T cell subsets, and analyzes their roles in infectious and inflammatory diseases.

In vivo expansion of regulatory T cell populations in IL-2-treated HIV patients

We have studied the long-term effects of IL-2 therapy on CD4⁺ T cell homeostasis and function in HIV patients. HIV-1 infection is characterized by a progressive decline in CD4⁺ T cells leading to a state of profound immunodeficiency. IL-2 therapy has been shown to improve CD4 counts beyond that observed with antiretroviral therapy. However, recent phase III trials revealed that despite a sustained increase in CD4 counts, IL-2-treated patients did not experience a better clinical outcome. To explain these disappointing results, we have studied phenotypic, functional, and molecular characteristics of CD4⁺ T cell populations in IL-2-treated patients. We found that the principal effect of long-term IL-2 therapy was the expansion of two distinct CD4⁺CD25⁺ T cell populations that shared phenotypic markers of CD4⁺CD25^hiFOXP3⁺ regulatory T cells (Treg), an immunosuppressive T cell subset critically important for the maintenance of self-tolerance, but could be distinguished by the levels of CD25 and FOXP3 expression. IL-2-expanded CD4⁺CD25⁺ T cells suppressed proliferation of effector cells in vitro and had gene expression profiles similar to Treg from healthy donors. Our data suggest that the sustained increase of the peripheral Treg pool in IL-2-treated HIV patients may account for the unexpected clinical observation that patients with the greatest expansion of CD4⁺ T cells had a higher relative risk of clinical progression to AIDS.

Single-cell gene profiling reveals heterogeneity of human CD4⁺ T cell subsets

For two decades, Th1 cells have been implicated in the pathogenesis of chronic inflammatory diseases. This notion has been challenged by the discovery of IL-23 and Th17 cells as key players in mouse autoimmune disease. In addition to IL-17, Th17 cells also produce the IL-10-related cytokine IL-22. However, recent reports have suggested that human IL-22-producing CD4⁺ T cells may represent a distinct T helper cell subset indicating an unexpected level of heterogeneity of CD4⁺ T cell "lineages".

Using single-cell analysis techniques, we have determined which human CD4⁺ T cell populations secrete IL-17, IL-22, and IFN-γ. Analysis of cytokine production at the single cell level revealed that only a small proportion of IL-22-producing cells also produced IL-17, whereas the major IL-22-secreting cell populations were a subset of Th1 cells and "Th22" cells that produce neither IL-17 nor IFN-γ. Finally, we identified a small population of CD4⁺ T cell producing the 3 cytokines. To define the molecular basis for the observed heterogeneity of inflammatory T cell subsets, we isolated individual IL-17A and IFN-γ-producing CD4⁺ T cells and analyzed the expression of marker genes for Th1, Th2, and Th17 subsets by single-cell gene profiling. Hierarchical clustering revealed that the gene expression profiles of Th1 and Th17 cells are distinct at the single-cell level. However, we observed large differences in the expression levels and a remarkable heterogeneity of the expression of marker genes for individual Th1 and Th17 cells. Our data revealed a striking heterogeneity of gene expression within inflammatory T cell populations, which may explain the diverse functions of CD4⁺ T cell subsets in orchestrating immune responses.

Linking genotype, cell function and pathology in inflammatory disease

Recent genome-wide association studies have shown that genetic variation at the IL-23R locus is strongly linked to several inflammatory diseases. However, the role of IL-23 in the differentiation and function of inflammatory T cell subsets and how IL23R variants affect IL-23 signaling remain unclear.

Ongoing studies focus on the role of distinct inflammatory T cell subsets in chronic inflammation using spondylarthropathies (SpA) as a model and to link genetic variations in the IL-23 signaling pathway to AS pathology. Combining genetic analysis with functional studies, we will link genotype, cell function and pathology in SpA.

Keywords: CD4⁺ T cell subsets, Th17 cells, Regulatory T cells, Cytokine signaling, Chromatin remodeling, Chronic inflammatory diseases, Autoimmunity, HIV

1. In vivo expansion of naive and activated CD4⁺CD25⁺FOXP3⁺ regulatory T cell populations in interleukin-2-treated HIV patients. (2010)

Weiss L, Letimier FA, Carriere M, Maiella S, Donkova-Petrini V, Targat B, Benecke A, Rogge L*, Levy Y*. [* Equal contribution]. Proc Natl Acad Sci U S A. 107(23):10632-7.. PMID: 20498045

2. The human COP9 signalosome protects ubiquitin-conjugating enzyme 3 (UBC3/Cdc34) from beta-transducin repeat-containing protein (betaTrCP)-mediated degradation (2010). Fernandez-Sanchez ME, Sechet E, Margottin-Goguet F, Rogge L, Bianchi E.. J Biol Chem. 285(23):17390-7.. PMID: 20378537

3. Integration of distinct intracellular signaling pathways at distal regulatory elements directs T-bet expression in human CD4⁺ T cells. (2009). Placek K, Gasparian S, Coffre M, Maiella S, Sechet E, Bianchi E, Rogge L.. J Immunol 183(12):7743-51.. PMID: 19923468

4. Genetic and epigenetic networks controlling T helper 1 cell differentiation. (2009). Placek K, Coffre M, Maiella S, Bianchi E, Rogge L.. Immunology 127(2):155-62. [Review]. PMID: 19476511

5. Chromatin remodeling by the SWI/SNF-like BAF complex and STAT4 activation synergistically induce IL-12Rbeta2 expression during human Th1 cell differentiation. (2007). Letimier FA, Passini N, Gasparian S, Bianchi E, Rogge L.. EMBO J. 26(5):1292-302.. PMID: 17304212