Regulation of self-tolerance and adaptive immunity by cell death and other cues

Division Of Basic Sciences - Nci

Investigators

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Abstract

B lymphocytes assemble the genes encoding for the antigen receptor (B cell receptor, BCR) during their development in the bone marrow. Once a diverse repertoire of naive B cells has been generated, only those B cells that can best respond to an antigenic challenge become activated, start to proliferate and some of those clones may also seed a germinal center (GC) reaction. GC B cells introduce mutations into the BCR-encoding genes and select for cells with increased antigen binding affinity. During these dynamic processes, memory B cells and high-affinity antibody producing plasma cells are also generated. B cell affinity maturation requires help from specialized T cells which are activated by dendritic cells (DCs). BCR assembly in the bone marrow and BCR mutation in GCs both result in the production of self-reactive B cells. How these potentially dangerous cells are controlled is a long-standing question that has puzzled immunologists. Our lab studies apoptosis as one proposed mechanism to delete self-reactive B cells. We have made progress in developing improved methods to detect autoreactivity and established new mouse models that will allow addressing these questions. Another potential mechanism to control self-reactive B cells is to inhibit their activity directly or indirectly for example by altering T cell activation by dendritic cells. Co-stimulatory molecules such as CD40 are expressed by both DCs and B cells, but the role CD40 plays in each cell type during autoimmune disease is not well understood. We contributed to a collaborative study dissecting the role of CD40 in DCs and B cells in experimental autoimmune encephalomyelitis resembling the human autoimmune disease multiple sclerosis. CD40 in dendritic cells was crucial for priming pathogenic T cells whereas CD40 in B cells made an independent contribution to the disease. Disease could be reconstituted in autoantigen-immunized mice lacking CD40 in B cells by transferring serum from diseased mice. We helped to trace this pathogenic contribution of B cells to IgG autoantibodies. Harnessing DCs for modulating immune responses first requires a basic understanding of DC biology. DCs have been difficult to study because they are extremely rare immune cells and come in different subsets. These include conventional DCs (cDCs) and plasmacytoid DCs (pDCs). Among cDCs, we further distinguish cDC1 and cDC2 subsets that differ in development and function. DC research has been greatly facilitated by the development of protocols to culture bone marrow precursors and differentiate them into DCs. Existing culture methods produce large numbers of DCs that allow experiments to dissect their biology. However, these DCs often do not correspond well to the DCs found in tissues, or they are complex mixtures of cDC1, cDC2 and pDCs, and thus require further purification steps. I have previously developed a new culture method called iCD103 that allows differentiating large numbers selectively of the cDC1 subset. This greatly facilitated research on this DC subset without the need for further purification and is now widely used in the field. I have contributed to a study highlighting current guidelines on the methods used for studying DC biology. A section on the iCD103 method is included in this publication.