THE ROLE OF DENDRITIC CELLS AND TYPE I INTERFERON IN THE GENERATION AND FUNCTION OF T FOLLICULAR HELPER CELLS
Abstract: Generation of long-lived plasma cells and memory B cells of high affinity takes place in germinal centers and depends on help from a specialized CD4+ T cell subset termed T follicular helper (Tfh) cells. These processes are crucial for long-term protection upon natural infection or in settings of vaccination, however they are also responsible for development of antibody-mediated autoimmune disease. Targeting of Tfh cells may therefore be of importance both in the development of new vaccines and in treatment of autoimmune conditions associated with pathologic autoantibody production. The aim of this thesis was to examine the molecular and cellular interactions in the generation and function of Tfh cells. First we wanted to determine if CXCR5+ Tfh cells are developmentally distinct from peripheral gut homing Th cells, and if they differ in terms of lymph node egress. We could observe that CXCR5+ Tfh cells and α4β7+ gut-homing Th cells are generated as two separate subsets and that majority of CXCR5+ Tfh cells were retained within the lymph node whereas the majority of α4β7+ Th cells exited. Second we looked at the role of type I interferon and dendritic cells in the generation and function of Tfh cells. We observed that type I interferon signaling in DCs is important for development of Tfh cells in response to antigen and TLR3 or TLR4 agonists and suggested that it functioned by inducing IL-6 production. We have also demonstrated that conventional CD11c DCs at least partially through their robust co-stimulation via CD28 provide unique signals essential for development of functional Tfh cells. A deeper knowledge of these processes would undoubtedly be valuable for the development of new vaccines as well as for advances in treatment of autoimmune diseases.
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