CD4+ T Cells Reactive to Enteric Bacterial Antigens in Spontaneously Colitic C3H/HeJBir Mice: Increased T Helper Cell Type 1 Response and Ability to Transfer Disease

Abstract

SummaryC3H/HeJBir mice are a new substrain that spontaneously develop colitis early in life. This study was done to determine the T cell reactivity of C3H/HeJBir mice to candidate antigens that might be involved in their disease. C3H/HeJBir CD4 ϩ T cells were strongly reactive to antigens of the enteric bacterial flora, but not to epithelial or food antigens. The stimulatory material in the enteric bacteria was trypsin sensitive and restricted by class II major histocompatibility complex molecules, but did not have the properties of a superantigen. The precursor frequency of interleuken (IL)-2-producing, bacterial-reactive CD4 ϩ T cells in colitic mice was 1 out of 2,000 compared to 1 out of 20,000-25,000 in noncolitic control mice. These T cells produced predominately IL-2 and interferon ␥ , consistent with a T helper type 1 cell response and were present at 3-4 wk, the age of onset of the colitis. Adoptive transfer of bacterial-antigen-activated CD4 ϩ T cells from colitic C3H/HeJBir but not from control C3H/HeJ mice into C3H/HeSnJ scid / scid recipients induced colitis. These data represent a direct demonstration that T cells reactive with conventional antigens of the enteric bacterial flora can mediate chronic inflammatory bowel disease.

Human Intestinal Epithelial Cells Are Broadly Unresponsive to Toll-Like Receptor 2-Dependent Bacterial Ligands: Implications for Host-Microbial Interactions in the Gut

“…Animal models of inflammatory bowel disease such as the IL-10 knockout mouse reconstituted with Gram-positive Enterococcus faecalis develop chronic intestinal inflammation (68,69). Finally, a substrain of C3H/HeJ mice which carry a mutation in the TLR4 gene and are LPS unresponsive develop chronic intestinal inflammation in the presence of commensal bacteria (70). These data suggest that Gram-positive bacteria or their products may play a role in the development or perpetuation of intestinal inflammation in the susceptible host.…”

Prevention of Experimental Colitis in SCID Mice Reconstituted with CD45RBhigh CD4+ T Cells by Blocking the CD40-CD154 Interactions

“…Wasting disease in this model can be abrogated after reducing the intestinal bacterial flora (24,26). Bacterial Ag-activated CD4 ϩ T cells from spontaneous colitic C3H/HeJBir mice, showing a Th1 phenotype of immune response, induce colitis after transfer into SCID mice (32). Thus, luminal bacterial Ags are the potential triggers of the inflammatory response in the SCID model, although it is not currently defined as to how these Ags trigger the initial CD4 ϩ T cell activation and expansion.…”

The role of T‐regulatory cells and Toll‐like receptors in the pathogenesis of human inflammatory bowel disease

“…For example, spontaneously colitic C3H/HeJBir mice (CBir), generated by selective breeding of C3H/HeJ mice for the colitic phenotype, show increased B-cell and T-cell reactivity towards bacterial antigens, 77 and transfer of CD4 + T cells from colitic CBir mice causes colitis in immunodeficient recipient mice. 78,79 This response is specific for commensal flora because the relevant T cells do not respond to food antigens or faecal extracts from germ-free mice. 80 A variety of clinical observations in IBD patients suggest that responses to commensal bacteria are also central to the development of human disease.…”