Elvira Kurmaeva1, Moheb Boktor, Songling Zhang, Richard Bao, Seth Berney, Dmitry V Ostanin. 1. *Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Sciences Center, Shreveport, Louisiana; †Division of Gastroenterology and Hepatology, Department of Medicine, Louisiana State University Health Sciences Center, Shreveport, Louisiana; and ‡Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana.
Abstract
BACKGROUND: L-selectin (CD62L) and β(7) integrins are important for trafficking of naive T cells under steady-state conditions. The objectives of this study were to dissect the requirements for T cell-associated CD62L and β(7) integrins during initiation, progression, and regulation of chronic colitis. METHODS: Using the T-cell transfer model, we compared colitogenic potential between T cells lacking one or both of these molecules with wild-type T cells. To assess trafficking of cells to the secondary lymphoid tissue and the gut, we performed co-homing experiments. RESULTS: Adoptive transfer of wild-type, CD62L(-/-) or β(7)(-/-) single-deficient T cells induced moderate to severe disease with slightly different kinetics. However, transfer of CD62L(-/-) β(7)(-/-) double-deficient (DKO) T cells produced significantly attenuated gut inflammation, which correlated with fewer T cells and reduced levels of proinflammatory cytokines in the colon lamina propria. Our subsequent experiments established that lack of colitogenic potential of these cells was due to inability of DKO T cells to home to the secondary lymphoid tissue. Furthermore, homing of in vitro-generated effector DKO T cells to the inflamed intestine was significantly impaired. Lastly, DKO regulatory T cells were ineffective at suppressing colitis induced by wild-type T cells. CONCLUSIONS: We established that T cells can use either CD62L(-/-) or β(7)(-/-) integrins to induce chronic colitis, but lack of both abrogates their colitogenic potential. Effector T cells critically rely on β(7) integrin during their recruitment to the inflamed intestinal mucosa. Finally, regulation of intestinal inflammation by regulatory T cells requires one or both of these adhesion molecules.
BACKGROUND:L-selectin (CD62L) and β(7) integrins are important for trafficking of naive T cells under steady-state conditions. The objectives of this study were to dissect the requirements for T cell-associated CD62L and β(7) integrins during initiation, progression, and regulation of chronic colitis. METHODS: Using the T-cell transfer model, we compared colitogenic potential between T cells lacking one or both of these molecules with wild-type T cells. To assess trafficking of cells to the secondary lymphoid tissue and the gut, we performed co-homing experiments. RESULTS: Adoptive transfer of wild-type, CD62L(-/-) or β(7)(-/-) single-deficient T cells induced moderate to severe disease with slightly different kinetics. However, transfer of CD62L(-/-) β(7)(-/-) double-deficient (DKO) T cells produced significantly attenuated gut inflammation, which correlated with fewer T cells and reduced levels of proinflammatory cytokines in the colon lamina propria. Our subsequent experiments established that lack of colitogenic potential of these cells was due to inability of DKO T cells to home to the secondary lymphoid tissue. Furthermore, homing of in vitro-generated effector DKO T cells to the inflamed intestine was significantly impaired. Lastly, DKO regulatory T cells were ineffective at suppressing colitis induced by wild-type T cells. CONCLUSIONS: We established that T cells can use either CD62L(-/-) or β(7)(-/-) integrins to induce chronic colitis, but lack of both abrogates their colitogenic potential. Effector T cells critically rely on β(7) integrin during their recruitment to the inflamed intestinal mucosa. Finally, regulation of intestinal inflammation by regulatory T cells requires one or both of these adhesion molecules.
Authors: Felix Becker; Elvira Kurmaeva; Felicity N E Gavins; Emily V Stevenson; Aaron R Navratil; Long Jin; Ikuo Tsunoda; A Wayne Orr; Jonathan S Alexander; Dmitry V Ostanin Journal: Inflamm Bowel Dis Date: 2016-06 Impact factor: 5.325
Authors: A Schippers; M Muschaweck; T Clahsen; S Tautorat; L Grieb; K Tenbrock; N Gaßler; N Wagner Journal: Mucosal Immunol Date: 2015-09-09 Impact factor: 7.313