How an immune cell repertoire physically computes

Computing is central to biological function at all scales, from proteins and cells to tissues and organisms. Our immune system encompasses all organizational scales to detect and respond quickly to invading pathogens. While detection is mediated by interaction between molecules, elicited responses rely on a dynamic repertoire of a variety of cells throughout the body, featuring a remarkable ability to adapt on the fly to unexpected challenges. Despite increasing knowledge of the parts, many basic questions about organization principles remain open. How much computation can be achieved on the receptor level for sensing and discrimination? Can active processes inside individual cells influence their collective evolution? What controls adaptability of an immune cell repertoire – both the limits and potential? Guided by in vivo observations, we build a theoretical framework that maps molecular recognition to clonal fitness via active force usage by the cell during signal acquisition. Our results suggest a physical origin for the apparent 'ineffectiveness' of clonal selection in vivo, revealing a multi-faceted role of active forces in limiting response potency while enabling phenotypic plasticity. This framework thus uncovers computational principles – at and across different scales – that balance the depth of response to current infection and breadth of coverage against future variants, within a finite repertoire.