DOI QR코드

DOI QR Code

Expression of IL-7RαlowCX3CR1+ CD8+ T Cells and α4β7 Integrin Tagged T Cells Related to Mucosal Immunity in Children with Inflammatory Bowel Disease

  • Da Hee Yang (Graduate School, Jeju National University College of Medicine) ;
  • Hyo Jin Kim (Department of Veterinary Medicine and Veterinary Medical Research Institute, Jeju National University) ;
  • Duong Thi Thuy Dinh (Department of Veterinary Medicine and Veterinary Medical Research Institute, Jeju National University) ;
  • Jiwon Yang (Department of Veterinary Medicine and Veterinary Medical Research Institute, Jeju National University) ;
  • Chang-Lim Hyun (Department of Pathology, Jeju National University College of Medicine) ;
  • Youngheun Jee (Department of Veterinary Medicine and Veterinary Medical Research Institute, Jeju National University) ;
  • Naeun Lee (Center for Integrative Rheumatoid Transcriptomis and Dynamics, The Catholic University of Korea) ;
  • Min Sun Shin (Department of Internal Medicine, Yale School of Medicine) ;
  • Insoo Kang (Department of Internal Medicine, Yale School of Medicine) ;
  • Ki Soo Kang (Department of Pediatrics, Jeju National University College of Medicine)
  • 투고 : 2024.05.30
  • 심사 : 2024.10.01
  • 발행 : 2024.11.15

초록

Purpose: The study aimed to investigate the recruiting of T lymphocytes including IL-7Rαlow CX3CR1+ effector memory (EM) CD8+ T cells and α4β7 integrin tagged T cells to inflamed intestinal mucosa. Methods: Whole blood and mucosal tissues of intestine were collected from 40 children with or without inflammatory bowel disease (IBD). T cell surface staining and immunohistochemistry were done with several antibodies in peripheral blood mononuclear cells (PBMCs) and intestinal mucosa, respectively. Serum levels of cytokines were measured by ELISA. Results: The frequency of IL-7RαlowCX3CR1+ EM CD8+ T cells in the PBMC was significantly higher in the ulcerative colitis group than in the control group (57.9±17.80% vs. 33.9±15.70%, p=0.021). The frequency of integrin α4β7+ CD4+ T cells in the PBMC was significantly lower in the ulcerative colitis group than in the control group (53.2±27.6% vs. 63.9±13.2%, p=0.022). Serum concentration of TNF-α was higher in the Crohn's disease group than in the control group (26.13±5.01 pg/mL vs. 19.65±6.07 pg/mL, p=0.008). Of the three groups, the ulcerative colitis group had the highest frequency of integrin α4β7+ T cells based on immunohistochemistry analyses for intestinal tissues, followed by the Crohn's disease group and the control group (4.63±1.29 cells vs. 2.0±0.57 cells vs. 0.84±0.52 cells, p<0.001). Conclusion: Trafficking immune cells with effector memory CD8+ T cells clarified by IL-7RαlowCX3CR1+ and integrin α4β7+ CD4+ T cells might be highly associated with the pathogenesis of ulcerative colitis.

키워드

과제정보

This work was supported by the Research Funds of Jeju National University Hospital (JNUH-2017) and the National Research Foundation of Korea grant funded by the Korea Government (NRF-2019R1F1A1063400).

참고문헌

  1. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009;361:2066-78.
  2. Perez-Lopez A, Behnsen J, Nuccio SP, Raffatellu M. Mucosal immunity to pathogenic intestinal bacteria. Nat Rev Immunol 2016;16:135-48.
  3. Zundler S, Becker E, Schulze LL, Neurath MF. Immune cell trafficking and retention in inflammatory bowel disease: mechanistic insights and therapeutic advances. Gut 2019;68:1688-700.
  4. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al.; GEMINI 2 Study Group. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 2013;369:711-21.
  5. Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al.; GEMINI 1 Study Group. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013;369:699-710.
  6. Panes J, Salas A. Past, present and future of therapeutic interventions targeting leukocyte trafficking in inflammatory bowel disease. J Crohns Colitis 2018;12(suppl 2):S633-40.
  7. Sans M, Danese S, de la Motte C, de Souza HS, Rivera-Reyes BM, West GA, et al. Enhanced recruitment of CX3CR1+ T cells by mucosal endothelial cell-derived fractalkine in inflammatory bowel disease. Gastroenterology 2007;132:139-53.
  8. Chang JT. Pathophysiology of inflammatory bowel diseases. N Engl J Med 2020;383:2652-64.
  9. Meenan J, Spaans J, Grool TA, Pals ST, Tytgat GN, van Deventer SJ. Altered expression of alpha 4 beta 7, a gut homing integrin, by circulating and mucosal T cells in colonic mucosal inflammation. Gut 1997;40:241-6.
  10. Ledder O, Assa A, Levine A, Escher JC, de Ridder L, Ruemmele F, et al. Vedolizumab in paediatric inflammatory bowel disease: a retrospective multi-centre experience from the Paediatric IBD Porto Group of ESPGHAN. J Crohns Colitis 2017;11:1230-7.
  11. Shin MS, You S, Kang Y, Lee N, Yoo SA, Park K, et al. DNA methylation regulates the differential xpression of CX3CR1 on human IL-7Rαlow and IL-7Rαhigh effector memory CD8+  T cells with distinct migratory capacities to the fractalkine. J Immunol 2015;195:2861-9.
  12. Kim HR, Hong MS, Dan JM, Kang I. Altered IL-7Rα expression with aging and the potential implications of IL-7 therapy on CD8+ T-cell immune responses. Blood 2006;107:2855-62.
  13. Kim HR, Hwang KA, Kim KC, Kang I. Down-regulation of IL-7Rα expression in human T cells via DNA methylation. J Immunol 2007;178:5473-9.
  14. Yang DH, Lee H, Lee N, Shin MS, Kang I, Kang KS. Effector memory CD8+  and CD4+  T cell immunity associated with metabolic syndrome in obese children. Pediatr Gastroenterol Hepatol Nutr 2021;24:377-83.
  15. Matsuoka K, Naganuma M, Hibi T, Tsubouchi H, Oketani K, Katsurabara T, et al. Phase 1 study on the safety and efficacy of E6011, antifractalkine antibody, in patients with Crohn's disease. J Gastroenterol Hepatol 2021;36:2180-6.
  16. Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol 2014;14:329-42.
  17. Tokita K, Shimizu H, Takeuchi I, Shimizu T, Arai K. Long-term efficacy and safety of golimumab for ulcerative colitis in a pediatric inflammatory bowel disease center in Japan. Pediatr Gastroenterol Hepatol Nutr 2022;25:461-72.
  18. Wang S, Wu C, Zhang Y, Zhong Q, Sun H, Cao W, et al. Integrin α4β7 switches its ligand specificity via distinct conformer-specific activation. J Cell Biol 2018;217:2799-812.
  19. Dotan I, Allez M, Danese S, Keir M, Tole S, McBride J. The role of integrins in the pathogenesis of inflammatory bowel disease: approved and investigational anti-integrin therapies. Med Res Rev 2020;40:245-62.
  20. Souza HS, Elia CC, Spencer J, MacDonald TT. Expression of lymphocyte-endothelial receptor-ligand pairs, α4β7/MAdCAM-1 and OX40/OX40 ligand in the colon and jejunum of patients with inflammatory bowel disease. Gut 1999;45:856-63.