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Our body responds to self and foreign agents through a myriad collection of effector cells and molecules that together form the immune system. The innate response is broad and occurs rapidly, whereas the adaptive response is slower, and it relies on highly specialized immune recognition of specific pathogens. Adaptive immune cells, like T cell and B cell lymphocytes possess a vast repertoire of antigen receptors called T cell receptors (TCR) and B cell receptors (BCR), respectively, where BCRs are also found in a secreted form as antibodies (Ab). The delicate balance of immune recognition lies in details, where minute changes in amino acid composition affect structure and function of antigen receptors. In this work, I dissect molecular details of three unconventional systems of immune recognition. Specifically, I present my molecular dissection of a newly identified protein from commensal microbes that engages host antibodies and has structural features of known superantigens but does not contribute to a pathogenic response. This interaction may provide an important function in the maintenance of host/microbiome gut balance. Additionally, I characterize homeostatic IgA and antigen-experienced IgG antibodies that naturally bind multiple diverse targets with low affinity and are thus called polyreactive. This work attempts to find the molecular basis for polyreactivity in natural antibodies and to emphasize the importance of embracing positive polyreactivity in antibody-based drug or vaccine design. Finally, I present my work on identifying the molecular mechanism behind butyrophilin-3 - γδTCR-dependent antigen recognition. Contrary to the canonical view of extracellular antigen presentation and direct recognition by T cells, the BTN3-γδTCR system involves intracellular sensing of molecules during cell stress. All findings in this thesis not only deepen our understanding of the myriad ways our immune system works, but also expand on the classical definitions of antigen-antibody and antigen-receptor interactions.




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