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We hypothesize that this failure is due to the absence of second signals provided by T cells following BCR stimulation. To address this, we developed an organoid screening system using HIS mouse splenocytes to identify missing signals. A combination of IL\u20104, IL\u201010, IL\u201021 together with CD40L was found to drive potent B cell proliferation and differentiation. Further organoid\u2010based screening revealed that TNF\u2010\u03b1 and CpG synergistically promoted IgG class\u2010switch, and that temporal separation of expansion and differentiation signals enhanced B cell responses. Translating these findings in vivo, CpG\u2010adjuvanted vaccination followed by sequential i.v. delivery of expansion and differentiation cytokine mixtures induced antigen\u2010specific B cell expansion, B cell differentiation, and IgG class\u2010switch in HIS mice without affecting non\u2010specific B cells. Sorting RBD\u2010specific B cells from immunized mice yielded recombinant antibodies with high binding affinity and neutralizing activity against SARS\u2010CoV\u20102 pseudovirus. Our study establishes a spleen organoid platform for screening factors that influence B cell responses in HIS mice and provides a generalizable strategy to obtain fully human antibodies for therapeutic development.<\/jats:p>","DOI":"10.1002\/advs.202524189","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T13:09:52Z","timestamp":1782479392000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimization of B Cell Responses in Human Immune System Mice Through Organoid Based Screening"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2573-9842","authenticated-orcid":false,"given":"Haiqiao","family":"Sun","sequence":"first","affiliation":[{"name":"National Resource Center for Mutant Mice MOE Key Laboratory of Model Animal for Disease Study Model Animal Research Center Department of Oncology Nanjing Drum Tower Hospital The Affiliated Hospital of 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