Effector memory CD4+T cells in mesenteric lymph nodes mediate bone loss in food-allergic enteropathy model mice, creating IL-4 dominance

• Published in: Mucosal immunology Vol. 14; no. 6; pp. 1335 - 1346
• Main Authors: Ono-Ohmachi, Aiko, Yamada, Satoki, Uno, Satoru, Tamai, Masato, Soga, Kohei, Nakamura, Shotaro, Udagawa, Nobuyuki, Nakamichi, Yuko, Koide, Masanori, Morita, Yoshikazu, Takano, Tomohiro, Itoh, Takumi, Kakuta, Shigeru, Morimoto, Chikao, Matsuoka, Shuji, Iwakura, Yoichiro, Tomura, Michio, Kiyono, Hiroshi, Hachimura, Satoshi, Nakajima-Adachi, Haruyo
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.11.2021; Nature Publishing Group US; Elsevier Limited
• Subjects: Allergology; Animal models; Animals; Antibodies; Biomarkers; Biomedical and Life Sciences; Biomedicine; Bone loss; Bone marrow; Bone Resorption - diagnostic imaging; Bone Resorption - etiology; Bone Resorption - metabolism; Bone Resorption - pathology; CD4 antigen; CD4-Positive T-Lymphocytes - physiology; Cytokines - genetics; Cytokines - metabolism; Diet; Disease Models, Animal; Disease Susceptibility; Effector cells; Food allergies; Food Hypersensitivity - complications; Food Hypersensitivity - immunology; Food Hypersensitivity - metabolism; Gastroenterology; Gene expression; Genetic crosses; Immunoglobulin E; Immunological memory; Immunology; Immunophenotyping; Inflammation; Interleukin 4; Interleukin-4 - genetics; Interleukin-4 - metabolism; Intestinal Diseases - complications; Intestinal Diseases - immunology; Intestinal Diseases - metabolism; Lymph nodes; Lymph Nodes - immunology; Lymph Nodes - metabolism; Lymphatic system; Lymphocytes; Lymphocytes T; Memory cells; Memory T Cells - physiology; Mesentery; Mice; Models, Biological; Monoclonal antibodies; mRNA; Osteoclasts; Osteoporosis; Ovalbumin; Spleen; Transgenes
• ISSN: 1933-0219; 1935-3456; 1935-3456
• DOI: 10.1038/s41385-021-00434-2

Intestinal inflammation can be accompanied by osteoporosis, but their relationship, mediated by immune responses, remains unclear. Here, we investigated a non-IgE-mediated food-allergic enteropathy model of ovalbumin (OVA) 23-3 mice expressing OVA-specific T-cell-receptor transgenes. Mesenteric lymph nodes (MLNs) and their pathogenic CD4+T cells were important to enteropathy occurrence and exacerbation when the mice were fed an egg-white (EW) diet. EW-fed OVA23-3 mice also developed bone loss and increased CD44hiCD62LloCD4+T cells in the MLNs and bone marrow (BM); these changes were attenuated by MLN, but not spleen, resection. We fed an EW diet to F1 cross offspring from OVA23-3 mice and a mouse line expressing the photoconvertible protein KikGR to track MLN CD4+T cells. Photoconverted MLN CD44hiCD62LloCD4+T cells migrated predominantly to the BM; pit formation assay proved their ability to promote bone damage via osteoclasts. Significantly greater expression of IL-4 mRNA in MLN CD44hiCD62LloCD4+T cells and bone was observed in EW-fed OVA23-3 mice. Anti-IL-4 monoclonal antibody injection canceled bone loss in the primary inflammation phase in EW-fed mice, but less so in the chronic phase. This novel report shows the specific inflammatory relationship, via Th2-dominant-OVA-specific T cells and IL-4 production, between MLNs and bone, a distant organ, in food-allergic enteropathy.