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Transcriptional networks controlling lymphocyte development

Final Report Summary - LYMPHOCONTROL (Transcriptional networks controlling lymphocyte development)

The adaptive immune system has a nearly unlimited capacity to respond to and protect us from environmental pathogens. The immune response to foreign antigens relies on a highly diverse immune cell repertoire that is generated through the random arrangement of antigen receptor genes in B and T cells. T cells patrol the body to recognize and eliminate pathogens by cell contact-mediated killing. B cells respond to foreign pathogens by terminally differentiating to plasma cells that secrete highly specific antibodies, which recognize and neutralize pathogens.

A plethora of transcription factors regulates the proper differentiation of hematopoietic progenitor cells along the B and T cell lineages as well as the recombination of antigen receptor genes. This ERC project aimed at investigating important transcription factors that control essential aspects of B cell development and function. To this end, we defined the physiological role of a given transcription factor by conditional mutagenesis and then used genome-wide transcription factor binding and gene expression data to identify the molecular mechanism by which the transcription factor contributes to the observed phenotype.

In this manner, we discovered that the transcription factors Pax5 and YY1 contribute to the generation of the vast B cell receptor repertoire of B cells by controlling the chromatin folding and efficient recombination of immunoglobulin genes. We identified Ikaros as critical regulator of an early checkpoint in B cell development. We discovered Bhlhe41 as the first transcription factor that controls the development, self-renewal and BCR repertoire of the innate-like B-1 cells. The B cell commitment factor Pax5 was shown to regulate all B cell immune responses by activating the expression of microRNAs that control B cell proliferation in response to extracellular signals. We demonstrated that the transcription factors E2A and E2-2 together control the development of plasma cells that secrete high-affinity antibodies. The plasma cell-specific transcription factor Blimp1 was shown to regulate many aspects of the generation and function of antibody-secreting plasma cells. Blimp1 was previously identified a risk factor for autoimmune diseases in humans. In agreement with this finding, we discovered in the mouse that premature Blimp1 expression in early B cell development is a likely mechanism, by which Blimp1 contributes to the development of autoimmune disease. Chromosomal translocations often generate new hybrid transcription factors with essential functions in cancer development. We demonstrated that the PAX5-ETV6 fusion protein functions as a potent oncoprotein in B cell leukemia by inducing a partial block of early B cell development and by activating B cell receptor signaling, which in turn promotes the survival and proliferation of the leukemic cells.

In summary, we deciphered the role of important transcription factors that play critical roles in early and late B lymphopoiesis, in terminally differentiated plasma cells as well as in the development of leukemia and autoimmunity.