Abnormal gut-associated lymphoid tissue (GALT) in humans is associated with infectious and autoimmune diseases, which cause dysfunction of the gastrointestinal (GI) tract immune system. To aid ininvestigating GALT pathologies invivo, we bioengineered a human-mouse chimeric model characterized by the development of human GALT structures originating in mouse cryptopatches. This observation expands our mechanistic understanding of the role of cryptopatches in human GALT genesis and emphasizes the evolutionary conservation of thisdevelopmental process. Immunoglobulin class switching to IgA occurs in these GALT structures, leading to numerous human IgA-producing plasma cells throughout the intestinal lamina propria. CD4+ Tcell depletion within GALT structures results from HIV infection, as it does in humans. This human-mouse chimeric model represents the most comprehensive experimental platform currently available for the study and for the preclinical testing of therapeutics designed to repair disease-damaged GALT.