BCRs (Abs) and TCRs (or adaptive immune receptors [AIRs]) are the means by which the adaptive immune system recognizes foreign and self-antigens, playing an integral part in host defense, as well as the emergence of autoimmunity. Importantly, the interaction between AIRs and their cognate Ags defies a simple key-in-lock paradigm and is instead a complex many-to-many mapping between an individual's massively diverse AIR repertoire, and a similarly diverse antigenic space. Understanding how adaptive immunity balances specificity with epitopic coverage is a key challenge for the field, and terms such as broad specificity, cross-reactivity, and polyreactivity remain ill-defined and are used inconsistently. In this Immunology Notes and Resources article, a group of experimental, structural, and computational immunologists define commonly used terms associated with AIR binding, describe methodologies to study these binding modes, as well as highlight the implications of these different binding modes for therapeutic design.
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