Augmenting adaptive immunity: progress and challenges in the quantitative engineering and analysis of adaptive immune receptor repertoires Alex J. Brown1,2, Igor Snapkov[,3, Rahmad Akbar[,3, Milena Pavlović3,4, Enkelejda Miho5,6,7, Geir K. Sandve4 Victor Greiff*,3 1 Department of Biomedical Research, National Jewish Health, Denver, CO, USA 2 Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA 3 Department of Immunology, University of Oslo, Oslo, Norway 4 Department of Informatics, University of Oslo, Oslo, Norway 5 Institute of Medical Engineering and Medical Informatics, School of Life Sciences, FHNW University of Applied Sciences and Arts Northwestern Switzerland, Muttenz, Switzerland 6 aiNET GmbH, Switzerland Innovation Park Basel Area AG, Basel, Switzerland 7 DayOne, BaselArea.swiss, Basel, Switzerland [ Equal Contribution * Correspondence:
[email protected] Abstract The adaptive immune system is a natural diagnostic and therapeutic. It recognizes threats earlier than clinical symptoms manifest and neutralizes antigen with exquisite specificity. Recognition specificity and broad reactivity is enabled via adaptive B- and T-cell receptors: the immune receptor repertoire. The human immune system, however, is not omnipotent. Our natural defense system sometimes loses the battle to parasites and microbes and even turns against us in the case of cancer and (autoimmune) inflammatory disease. A long-standing dream of immunoengineers has been, therefore, to mechanistically understand how the immune system “sees”, “reacts” and “remembers” (auto)antigens. Only very recently, experimental and computational methods have achieved sufficient quantitative resolution to start querying and engineering adaptive immunity with great precision. In specific, these innovations have been applied with the greatest fervency and success in immunotherapy, autoimmunity and vaccine design.