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The developmental program that commits a hematopoietic stem cell to the B lymphocyte lineage employs transcriptional regulators to enable the assembly of an antigen receptor complex with a useful specificity and with signalling competence. Once a naive IgM+ B cell is generated, it must correctly integrate signals from the antigen receptor with those from cytokine receptors and co-receptors delivering T cell help. The B cell responds through the regulated expression of genes that implement specific cell expansion and differentiation, secretion of high levels of high-affinity antibody, and generation of long-term memory.
Pucillo’s laboratory uses biochemical, cellular and molecular approaches to elucidate the molecular pathways that regulate B cell activation and development. With particular emphasis on the transcription factors specific of B cells, as Pax5 and EBF, or essential for B cell, as NF-κB, that impact on this processes. The current challenge is the identification of target genes that are activated to implement the correct response and how few transcription factors differentially activate multiple genes sets following specific external stimula through a specific enhanceosome formation, different for each expressed gene for the composition or for a single protein post-translational modification which alterate the DNA recognition of transcriptional complex
Moreover, Pucillo’s lab investigate the signal transduction pathways elicited by T-B cell interaction via CD40-CD154. CD40 is a B cell surface receptor that belongs to the pleiotropic tumor necrosis factor receptor (TNFR) superfamily. It is expressed on B cells and certain accessory cells. The interaction between CD40 and its ligand (CD154), which is expressed on activated CD4+ T cells, is critical in the regulation of immune response. Engagement of CD40 on B lymphocytes promotes proliferation, cytokine production, upregulation of various surface molecules involved in antigen presentation, germinal center and memory B cell formation antibody isotype switching and affinity maturation and the B cell life span. The various biological activities induced via CD40 are mediated through TNF receptor-associated factors (TRAF). The signal transduction through surface CD40 is not clearly understood. However, one of the major final outcomes is an alteration in the activity of one or more transcription factors, and hence it is generally believed that CD40 achieves many of its complex effects on B cells through alterations in gene expression. CD40 stimulation activates B cells and promotes various aspects of a functional humoral immune response, including enhancement of survival and proliferation.
Most recently his laboratory has expanded their interest in the study the role of Mast cell as an antenna of microenvironment and subsequently in the regulation of the adaptive response of the tissue as well as release chemical mediator which act as modulator of immune response. This body of work may provide a conceptual framework to therapeutically manipulate these responses in the settings of autoimmune disease and cancer.
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