CTCF: A Crucial Regulator of Gene Expression in Lymphocytes

In vertebrates, the immune system is responsible for the protection against pathogens such as viruses, bacteria, fungi or parasites. This remarkably effective defense system depends upon the white blood cells or leukocytes, which mediate both innate and adaptive immune responses. Innate immunity provides an immediate but non-specific front line of host defense against many pathogens and involves granulocytes (neutrophils, eosinophils and basophils), mast cells, macrophages and natural killer (NK) cells. Germ lineencoded surface receptors to common pathogens constituents on innate effector cells trigger the elimination of pathogens by phagocytosis and the release of inflammatory mediators, such as cytokines and chemokines. These receptors are referred to as pattern recognition receptors (PRRs), which recognize a limited set of molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). Acquired or adaptive immunity is characterized by gradual, though highly specific and effective immune responses against pathogens. Three major cell types are involved in adaptive immunity: B-lymphocytes, T-lymphocytes and antigen presenting cells (APCs), the most potent of which are dendritic cells (DCs). DCs act as messengers between the innate and adaptive immune system. Their main function is to take up, process and present pathogen constituents (also called antigens) with major histocompatibility complex (MHC) proteins to T lymphocytes. B- and T-lymphocytes are considered to be the central players of the adaptive immune system. Their unique and virtually limitless capacity to specifically recognize antigens relies on the generation of a wide repertoire of antigen receptors – B-cell receptor (BCR) in B-lymphocytes and T-cell receptor (TCR) in T-lymphocytes – during lymphocyte development. B-lymphocytes respond to pathogens by producing large quantities of antibodies (secreted form of BCR) with pathogen neutralizing capacities, when terminally differentiated into plasma cells. In response to antigens, T-lymphocytes produce cytokines that direct the immune response (T-helper cells) or toxic granules that induce the death of pathogen infected cells (cytotoxic T-cells). Following pathogen elimination, lymphocytes leave a lasting legacy of the antigens they have encountered in the form of memory cells, which are able to mount faster and stronger immune responses in subsequent challenges with the same antigen – a process know as immunological memory. This thesis focuses on the role of specific transcription factors during lymphocyte development and differentiation into functional effector subsets.

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