Senescence-associated decline of lymphocyte migration in gut-associated lymphoid tissues of rat small intestine.

Scenescence-induced changes in gut-associated lymphoid tissues may contribute largely to the impaired immune responses during aging. Age-related changes in lymphocyte recirculations were investigated in Peyer's patches of rat small intestine. Cell dynamics of labeled T lymphocytes were observed under an intravital fluorescence microscope and compared between young and aged rats. Lymphocyte transport through intestinal lymph was decreased in aged rats. The lymphocyte rolling and adherence in postcapillary venules (PCV) of Peyer's patches was also significantly impaired in aged rats, with decreased expression of L-selectin on lymphocyte surfaces. Immunohistochemical analysis revealed a significant decrease in the CD8-positive cell population in Peyer's patches of the aged group, although mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression in postcapillary venules was unaltered. Lymphocyte adoptive-transfer studies indicated that although both the donor and recipient factors influence the adherence of T cells, the former may play a predominant role in the age-related change. This study clearly demonstrated in situ that T cell migration into Peyer's patches is significantly decreased in the aged intestine, which may reflect the impaired immune responses in the aging process.

Exposure to fatty acids modulates interferon production by intraepithelial lymphocytes.

Intraepithelial lymphocytes (IELs) play important roles in intestinal mucosal immunity. Although fatty acids are known to modulate the functions of immune effector cells, there has been no information about how fat exposure affects immunological function of IELs. In this study, we examined how fatty acids of various chain lengths modulate the production of interferon (IFN)-gamma by IELs stimulated with T-cell receptor (TCR) or interleukin (IL)-12/IL-18. IELs isolated from the small intestine of BALB/c mice were stimulated with plate-coated anti-CD3 monoclonal antibody (mAb) or IL-12/IL-18. They were coincubated in microtiter plates for 3 days with various concentrations of fatty acid micelles. We used arachidonic acid, linoleic acid, and oleic acid as long-chain fatty acids, and used octanoic acid as a medium-chain fatty acid. IFN-gamma in the supernatants were measured by ELISA, and the expression of IFN-gamma mRNA in IELs was determined by RT-PCR. Significant production of IFN-gamma from IELs was observed after anti-CD3 mAb stimulation. The combination of IL-12 and IL-18 induced significant levels of IFN-gamma production without TCR stimulation. Increased IFN-gamma mRNA was also observed after anti-CD3 or IL-12/IL-18 stimulation. Long-chain fatty acids dose-dependently inhibited the stimulated-IFN-gamma production at concentrations greater than 10 micro M, but the medium-chain fatty acid did not cause any significant changes in IFN-gamma production. IFN-gamma production from gammadelta IELs was very low compared with alphabeta IELs, however, both populations showed similar attenuating patterns when treated with long-chain fatty acids. There is a possibility that the exposure of IELs to intraluminal fatty acids significantly modifies the immune function of intestinal mucosa.

Spatial heterogeneity of TNF-alpha-induced T cell migration to colonic mucosa is mediated by MAdCAM-1 and VCAM-1.

Relatively little is known about how recirculation of lymphocytes through the inflamed intestinal mucosa is regulated. The aim of this study was to investigate the dynamic process of T lymphocyte-endothelial cell adhesion in TNF-alpha-challenged murine colonic mucosa by intravital microscopy. T lymphocytes from spleen (SPL) and intestinal lamina propria (LPL) were fluorescence labeled, and their adhesion to microvessels in the colonic mucosa was observed. In TNF-alpha (25 microg/kg)-stimulated colonic venules, an enhanced adhesion of SPL and LPL was demonstrated, with dominant recruitment of LPLs. The magnitude of the increased LPL adhesion was more significant in the colon than in the small intestine. These T lymphocyte interactions in the colonic mucosa were significantly reduced by blocking MAbs against either mucosal addressin cell adhesion molecule-1 (MAdCAM-1), VCAM-1, alpha(4)-integrin, or beta(7)-integrin but not by anti-ICAM-1. Immunohistochemistry revealed significant MAdCAM-1 expression in the lamina propria and VCAM-1 expression in the submucosa of TNF-alpha-treated colon. Spatial heterogeneity of MAdCAM-1 and VCAM-1 activation following TNF-alpha challenge may promote specific T lymphocyte recruitment in the inflamed colonic mucosa.

Intravital observation of adhesion of lamina propria lymphocytes to microvessels of small intestine in mice.

BACKGROUND & AIMS: Although the recirculation of lymphocytes through the intestinal mucosa is important for the specific immune defense, the homing of lamina propria lymphocytes (LPLs) has not been clearly understood. The aim of this study is to compare, under an intravital microscope, the dynamic process of lymphocyte-endothelium recognition and binding in the murine intestinal mucosa of T lymphocytes from the lamina propria of intestine to that of T lymphocytes from the spleen. METHODS: LPLs isolated from nonlymphoid areas of the small intestine and spleen (SPL) were fluorescence-labeled and injected into a jugular vein of recipient mice. Microvessels of the villus mucosa and ileal Peyer's patches were observed under an intravital fluorescence microscope, and the effects of anti-adhesion-molecule antibodies on lymphocyte-endothelial interaction were investigated. RESULTS: LPLs accumulated abundantly in the microvessels of villus tips but not in the submucosal venules or postcapillary venules of Peyer's patches, where SPLs migrated selectively. The accumulation of LPLs in the villus tips was almost completely inhibited by anti-beta7-integrin and was significantly inhibited by anti-mucosal addressin cell-adhesion molecule 1 (MAdCAM-1) and anti-alpha4-integrin. Significant MAdCAM-1 expression was observed in the microvessels of the villus mucosa. Some SPLs adhered to the nonlymphoid mucosa, but most soon detached. CONCLUSIONS: It was shown in vivo for the first time that T lymphocytes from the lamina propria but not from the spleen adhere selectively, mostly via alpha4beta7 and MAdCAM-1, to the microvessels of villus tips of the intestine, but not to the postcapillary venules of Peyer's patches.