Dysregulated luminal bacterial antigen-specific T-cell responses and antigen-presenting cell function in HLA-B27 transgenic rats with chronic colitis.
HLA-B27/beta2 microglobulin transgenic (TG) rats spontaneously develop T-cell-mediated colitis when colonized with normal commensal bacteria, but remain disease-free under germ-free conditions. We investigated regulation of in vitro T-cell responses to enteric bacterial components. Bacterial lysates prepared from the caecal contents of specific pathogen-free (SPF) rats stimulated interferon-gamma (IFN-gamma) production by TG but not non-TG mesenteric lymph node (MLN) cells. In contrast, essentially equivalent amounts of interleukin-10 (IL-10) were produced by TG and non-TG cells. However, when cells from MLNs of non-TG rats were cocultured with TG MLN cells, no suppression of IFN-gamma production was noted. Both non-TG and TG antigen-presenting cells (APC) pulsed with caecal bacterial lysate were able to induce IFN-gamma production by TG CD4+ cells, although non-TG APC were more efficient than TG APC. Interestingly, the addition of exogenous IL-10 inhibited non-TG APC but not TG APC stimulation of IFN-gamma production by cocultured TG CD4+ lymphocytes. Conversely, in the presence of exogenous IFN-gamma, production of IL-10 was significantly lower in the supernatants of TG compared to non-TG APC cultures. We conclude that commensal luminal bacterial components induce exaggerated in vitro IFN-gamma responses in HLA-B27 TG T cells, which may in turn inhibit the production of regulatory molecules, such as IL-10. Alterations in the production of IFN-gamma, and in responses to this cytokine, as well as possible resistance of TG cells to suppressive regulation could together contribute to the development of chronic colitis in TG rats.
Qian
Bi-Feng
BF
Center for Gastrointestinal Biology and Disease, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
Tonkonogy
Susan L
SL
Hoentjen
Frank
F
Dieleman
Levinus A
LA
Sartor
R Balfour
RB
D000818:Animals; D030801:Animals, Genetically Modified; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000942:Antigens, Bacterial / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002432:Cecum / Q000276:immunology / Q000382:microbiology; D002478:Cells, Cultured; D002908:Chronic Disease; D018920:Coculture Techniques; D003092:Colitis / Q000276:immunology* / Q000382:microbiology; D005260:Female; D005856:Germ-Free Life; D015796:HLA-B27 Antigen / Q000032:analysis* / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D000942:Antigens, Bacterial; D015796:HLA-B27 Antigen; D016753:Interleukin-10; D007371:Interferon-gamma