The main focus of the Bettelli Lab is to identify the cell types of the immune system and mechanisms, which induce and regulate the development of autoimmunity.
Mechanisms of T cell differentiation and pathogenicity
Upon activation, CD4+ T cells differentiate in different subsets of effector T helper (Th) cells which produce selective cytokines (IFN-g, IL-17, GM-CSF) and have specialized effector functions. Each subset of Th cells orchestrates a specific immune response dedicated to clear pathogens, but when dysregulated, can also lead to the development of autoimmune and allergic reactions. CD4+ Th cell differentiation is driven by local cytokine environment. T cells producing IL-17 have been implicated in several autoimmune diseases including rheumatoid arthritis (RA), multiple sclerosis (MS), and psoriasis. Few years ago, Dr. Bettelli identified the cytokines IL-6, TGF-b and IL-23, which drive the differentiation and pathogenicity of Th17 cells. Recent studies have demonstrated that pathogenic Th cells also secrete GM-CSF. The Bettelli Lab is currently determining whether and how GM-CSF+ Th cells differ from IFN-g+ and IL-17+ Th cells and how they mediate their pathogenic functions in autoimmune diseases.
Mechanisms of T cell regulation
Regulatory T cells (Treg) expressing the transcription factor Foxp3 are T cells which, in healthy individuals, keep CD4+ T cells in check. In patients with autoimmune diseases, Tregs are not as effective as in healthy individuals, and CD4+ T cells have an effector/memory phenotype and produce cytokines such as IFN-g, IL-17 and GM-CSF. Although the mechanisms by which Tregs control naïve CD4+ T cells have been well described, the mechanisms by which Tregs control effector/memory Th1, Th17 cells is not well understood. The Bettelli Lab has discovered that Th cells producing IFN-g, IL-17 and GM-CSF are differentially regulated by Tregs during the course of central nervous system (CNS) autoimmunity. Ongoing research in the laboratory focus on determining the mechanisms by which Tregs can control efficiently and specifically effector/memory T cells producing IFN-g, IL-17 or GM-CSF and how these effector/memory T cells can themselves impact Treg functions.
Modulation of the immune response by STAT1
Signal transducer and activator of transcription 1 (STAT1) is a transcription factor activated by type I and II interferons. This response needs to be fine-tuned because diminished or excessive STAT1-mediated signaling leads to enhanced susceptibility to viral, bacterial and fungal infections and the development of autoimmune diseases. Using loss and gain of function models, the Bettelli Lab is currently investigating how STAT1-mediated signaling modulates the function of different immune cells and participate in the pathogenesis of different autoimmune diseases.
Control of the immune response by DOCK8
Dedicator of cytokinesis 8 (DOCK8) is a guanine nucleotide exchange factor expressed in hematopoietic cells. DOCK8 deficiency is characterized by allergic inflammation and susceptibility towards infections, autoimmunity and malignancy. The Bettelli Lab has been studying the mechanisms by which DOCK8 modulates the function of adaptive and innate cells and further contributes to the progression of autoimmunity.