Regulatory properties of dendritic cells and B cells in adaptive immunity

Abstract: This thesis is based upon four original papers in which human dendritic cells (DCs) and B cells have been analyzed in terms of how they influence the character of adaptive immune responses. DCs isolated from human tonsils were found to possess a capacity to directly regulate proliferation, isotype switching, and antibody production in B cells. DC-produced cytokines, including IL-13, were identified as critical mediators of these B cell responses. Furthermore, gene chip technology was used to evaluate the nature and kinetics of the global gene expression taking place in monocyte-derived DCs exposed to inflammatory agents. Obtained results revealed an extensive and temporal reprogramming of these cells in response to TNF-a, IL-1b, plus mediators released by activated monocytes. The altered gene expression was represented by a pronounced upregulation of a number of mRNAs encoding proteins with established functions in the regulation of both T and B cell responses. This transcriptional reorganization may reflect the effect of in vivo released inflammatory mediators, indicating that DCs can be fully matured to activate adaptive immunity in response to tissue inflammation. Furthermore, also the role of B cells in immune regulation was investigated. Antigen-activated B cells within germinal centers (GC) were found to produce the Th2-polarizing cytokine IL-4 and consequently they could elicit Th2-differentiation in vitro. In agreement with this in vitro observation, a Th2 precursor subset was identified in human tonsil and demonstrated to uniformly display a GC-associated CXCR5high phenotype. Therefore Th2-development in human tonsils appears to selectively occur within GCs and to be supported by B cells secreting IL-4. Moreover, IL-4-producing B cells were also identified within follicles located in colon mucosa, indicating that B cell-dependent Th2 development can take place in several of the mucosa associated lymphoid tissues. Finally, functional properties of the previously described CD57+ GC Th cells were addressed and obtained results showed that these cells represent anergized T cells. These data thus suggest that B cells and GCs regulate CD4+ T cell differentiation in a finely tuned fashion, either by promoting differentiation of Th2 cells or by furnishing T cell-unresponsiveness. In conclusion, I propose that Th cell polarization may be subjected to a counterbalanced regulation, where DC-produced IL-12 and/or IFN-a/b promote Th1-differentiation, whereas GCs and B cells preferentially furnish Th2-development but also contribute to suppression of T cell responses.