Cryptopatches Are Essential for the Development of Human GALT

• Published in: Cell reports (Cambridge) Vol. 3; no. 6; pp. 1874 - 1884
• Main Authors: Nochi, Tomonori, Denton, Paul W., Wahl, Angela, Garcia, J. Victor
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.06.2013; Elsevier
• Subjects: Animals; CD4-Positive T-Lymphocytes - immunology; Cell Differentiation - immunology; Gastrointestinal Tract - cytology; Gastrointestinal Tract - growth & development; Gastrointestinal Tract - immunology; HIV Infections - immunology; Humans; Intestinal Mucosa - cytology; Intestinal Mucosa - growth & development; Intestinal Mucosa - immunology; Intestinal Mucosa - pathology; Lymphocyte Activation - immunology; Lymphoid Tissue - growth & development; Lymphoid Tissue - immunology; Mice
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.05.037

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 in investigating GALT pathologies in vivo, 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 this developmental 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+ T cell 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. [Display omitted] [Display omitted] •Cryptopatches are a required scaffold/foundation wherein human GALT develops•Plasma cells differentiated in human GALT migrate to the intestinal lamina propria•Human GALT generates human plasma cells producing either human IgA1 or IgA2•HIV infection leads to massive CD4+ T cell loss within human GALT Human GALT genesis is poorly understood. Here, Garcia and colleagues show that human GALT develops in cryptopatches of NOD/SCID-BLT humanized mice. These human GALT structures are populated with human B, T, macrophage, and dendritic cells. Ig class switching in the GALT results in human IgA1+ and IgA2+ cells in the intestinal lamina propria. These results define an essential role for cryptopatches in human GALT development. In addition, HIV infection results in specific human CD4+ T cell depletion in GALT.