Search

Glucocorticoid-induced TNF receptor family-related protein (GITR) regulates the function of both T cells and antigen-presenting cells (APCs), while the function of GITR ligand (GITR-L) is largely unknown. Here we evaluate the role of GITR-L, whose expression is restricted to APCs, in the development of enterocolitis. On injecting naive CD4+ T cells, GITR-L-/- Rag-/- mice develop a markedly milder colitis than Rag-/- mice, which correlates with a 50% reduction of Ly6C+CD11b+MHCII+ macrophages in the lamina propria and mesenteric lymph nodes. The same result was observed in αCD40-induced acute colitis and during peritonitis, suggesting an altered monocyte migration. In line with these observations, the number of nondifferentiated monocytes was approximately 3-fold higher in the spleen of GITR-L-/-Rag-/- mice than in Rag-/- mice after αLCD40 induction. Consistent with the dynamic change in the formation of an active angiotensin 1I type 1 receptor (AT1) dimer in GITR-L-/- splenic monocytes during intestinal inflammation, the migratory capability of splenic monocytes from GITR-L-deficient mice was impaired in an in vitro transwell migration assay. Conversely, αGITR-L reduces the number of splenic Ly6Chi monocytes, concomitantly with an increase in AT1 dimers. We conclude that GITR-L regulates the number of proinflammatory macrophages in sites of inflammation by controlling the egress of monocytes from the splenic reservoir. [ABSTRACT FROM AUTHOR]

According to the ‘hygiene hypothesis’, enhanced microbial exposure due to early childhood infections leads to a reduction of Th2-mediated allergic diseases and inflammatory bowel disease. To begin to elucidate the mechanisms underlying this hypothesis, we studied development of Th2-mediated colitis of the TCRα knockout (KO) mouse in both a specific pathogen-free (SPF) facility and a conventional (CV) facility. After more than five generations in each facility, TCRα KO mice kept in the CV facility developed dramatically less colitis than mice that were kept in the SPF facility. Surprisingly, the suppression of colitis in the CV facility correlated with a significant increase in natural IgM production by B-1 B cells. In contrast, B cell-deficient TCRα double-knockout (αμ DKO) mice maintained in the CV facility continued to develop severe colitis, strongly suggesting that B-1 B cells contributed to the suppression of colitis. Indeed, the adoptive transfer of B-1 B cells isolated from the peritoneal cavity of TCRα KO mice (SPF) into αμ DKO mice (CV) suppressed the development of colitis in the recipient mice. We conclude that B-1 cells play a regulatory role in Th2-mediated colitis under non-hygienic conditions, possibly by generating natural antibodies in response to microbial flora. [ABSTRACT FROM AUTHOR]