Failure of T cell homing, reduced CD4/CD8alphaalpha intraepithelial lymphocytes, and inflammation in the gut of vitamin D receptor KO mice.
Specific pathogen-free IL-10 KO mice failed to develop inflammatory bowel disease (IBD), whereas IL-10/vitamin D receptor (VDR) double KO mice developed fulminating IBD. WT CD4 T cells inhibited experimental IBD, while VDR KO CD4 T cells failed to suppress IBD. VDR KO mice had normal numbers and functions of regulatory T cells. The percentages of IL-17- and IFN-gamma-secreting T cells in the gut of mice reconstituted with WT and VDR KO CD4 T cells were also not different. Instead, there were twice as many CD8alphaalpha intraepithelial lymphocytes (IEL) in mice that were reconstituted with WT CD4 T cells than in mice reconstituted with VDR KO CD4 T cells. Furthermore, VDR KO mice had reduced numbers of CD8alphaalpha IEL, absent CD4/CD8alphaalpha populations, and as a result low IL-10 production in the IEL. The lack of CD8alphaalpha IEL was due in part to decreased CCR9 expression on T cells that resulted in the failure of the VDR KO T cells to home to the small intestine. We conclude that the VDR mediates T cell homing to the gut and as a result the VDR KO mouse has reduced numbers of CD8alphaalpha IEL with low levels of IL-10 leading to increased inflammatory response to the normally harmless commensal flora.
Yu
Sanhong
S
Center for Immunology and Infectious Disease, Department of Veterinary and Biomedical Science, Pennsylvania State University, University Park, PA 16802, USA.
Bruce
Danny
D
Froicu
Monica
M
Weaver
Veronika
V
Cantorna
Margherita T
MT
D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology*; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D054388:Receptors, CCR / Q000235:genetics / Q000276:immunology; D018167:Receptors, Calcitriol / Q000235:genetics / Q000276:immunology*
C119309:CC chemokine receptor 9; D015704:CD4 Antigens; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D054388:Receptors, CCR; D018167:Receptors, Calcitriol