Pattern recognition and iNKT cell regulation of B cell activation

The immune system protects individuals against infections but can cause disease if the response is unbalanced. Immune responses include both innate and adaptive response, and these systems are connected. As the first line of defense, innate immune responses are immediately induced upon infection. In contrast, adaptive immune responses respond to antigens in a delayed but more specific and effective. The adaptive immune responses are classified into T-independent and T-dependent responses, and B cells play a vital role in antigen presentation and antibody production in both types of immune responses. Moreover, B cells are crucial in maintaining immune tolerance, and unregulated B cells may enhance autoimmune disorders. This thesis focuses on B cell regulation in immune responses. Paper I identifies a novel interaction of scavenger receptor CD36 with LC3B regulating autophagosome generation in B cells in adaptive immune responses. CD36-deficient B cells exhibited a significantly reduced formation of plasma cells (PCs) and altered metabolism. These changes are accompanied by the impaired formation of autophagosomes. Autophagy induction led to colocalization of CD36 with autophagosome membrane protein LC3. Mice lacking CD36 in B cells had reduced germinal center (GC) responses and autophagosomes in GC B cells in vivo. Paper II shows that B cell response to apoptotic cells (ACs) relies on endosomal pattern recognition receptors. Syngeneic AC injections were used to break tolerance, and unc93b1 mutant mice that lack signaling from the TLR3, TLR7, and TLR9 receptors were investigated. Autoantibodies against Ro-52/60, La, cardiolipin, and DNA were all lower in unc93b1 mutant mice. We also observed significantly less formation of GC B cells and follicular help T (Tfh) cells in unc93b1 mutant mice than WT mice. Paper III reveals a balance between conventional and unconventional Tfh cells direct autoreactive B cells. Coadministration of α-GalCer with ACs initiated follicular helper iNKT (iNKTfh) cell formation, which promoted short-lived GC B cells and IgG1 autoantibody production while restricted Tfh cells. We also observed that deletion of CD1d specifically in B cells limited early B cell activation, iNKTfh cell generation, GC B cell formation, and auto-antibody production. Moreover, endosomal TLRs were required for iNKTfh cell-regulated GC response. In this thesis, we collectively evaluated the role of CD36, TLR3/7/9, and CD1d in regulating B cells in immune or autoimmune responses. It identifies critical players of CD36 in T-dependent immune response, TLR3/7/9 in autoimmunity, and iNKTfh cell-mediated help to autoreactive B cells. These studies contribute to our understanding of the connection between innate and adaptive immune responses