Functional adaptation of intrathymically differentiating B cells for central T cell tolerance

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Thymic stromal cells display a number of unique cell-biological and molecular features that seem to have evolved to support specific aspects of T cell differentiation. Cortical thymic epithelial cells use unique proteases for the generation of MHC class I- or II-bound peptides that are required for normal positive selection. Medullary thymic epithelial cells express the Autoimmune regulator (Aire) gene and thereby ectopically express peripheral tissue antigens for central tolerance induction. Certain migratory dendritic cell subsets may further increase the scope of central tolerance by carrying peripheral antigens into the thymus. Besides these intensely studied stromal components, the thymus also harbors other, less well investigated stromal cell types such as B cells. Interestingly, rather than being a result of immigration of blood-derived B cells that have differentiated in the bone marrow (BM), the majority of thymic B cells instead seem to arise through intrathymic B lymphopoiesis. Some reports have indicated that antigen presentation by thymic B cells can lead to clonal deletion of T cells. Nevertheless, it is unclear whether thymic B cells merely represents an epiphenomenon resulting from the developmental plasticity of early T cell progenitors or instead reflect a true physiological requirement of a functionally specialized thymic B cell lineage. In support of the latter idea, our preliminary work has revealed several remarkable differences between thymic B cells and BM-derived mainstream B cells. Thus, intrathymically differentiating B cells, in contrast to their counterparts in the BM or secondary lymphoid organs, express high levels of MHC class II and co-stimulatory molecules. Most surprisingly, however, we found that a substantial fraction of B cells in the thymus, but not in the BM or the spleen, express Aire-mRNA and -protein. On this basis, we hypothesize that thymic B lymphopoiesis does not simply duplicate mainstream B cell differentiation in the BM, but leads to the emergence of distinct molecular and phenotypic characteristics related to a critical function of thymic B cells for T cell tolerance. In the proposed work, we want to (i) address whether and how Aire-expression and other tolerogenic features of thymic B cells are orchestrated through microenvironment-specific extrinsic cues, (ii) characterize the Aire-dependent and Aire-independent molecular and phenotypic signature of thymic B cells as compared to bone marrow-derived B cells and (iii) investigate how Aire-dependent and Aire-independent features of thymic B cells relate to CD4 T cell tolerance.