Lymphocyte migration plays a key role in the generation of a mucosal immune response.

摘要

Lymphocyte migration into lymphoid tissues is critical for maintaining proper lymphocyte distribution and initiating rapid immune responses. This process is largely regulated by two adhesion molecules, L-selectin and beta 7 integrin. Mice deficient in L-selectin (L-selectin-/-) have normal mucosal antibody responses, but decreased peripheral responses while beta7 integrin-/- mice have normal peripheral, but decreased mucosal responses. Importantly, mice deficient in both receptors (L-selectin/beta7 integrin-/-) demonstrate further decreases in both peripheral and mucosal antibody responses. While these decreases correlate with significant reductions in tissue-specific lymphocyte migration, it remains unclear whether lack of lymphocyte migration alone accounts for the reduced responses. Therefore, the organization of lymphoid tissues, including M cells and dendritic cells, the formation of germinal centers, and susceptibility to challenge with Salmonella typhimurium, were examined in adhesion molecule deficient mice. Immunofluorescence microscopy revealed the presence of B cells and CD4+ and CD8+ T cells in lymphoid tissues of all genotypes of mice. Interestingly, Peyer's patches from both beta7 integrin-/- and L-selectin/beta 7 integrin-/- mice contained small, hypocellular follicles, while mesenteric lymph nodes (MLN) from L-selectin/beta 7 integrin-/- mice, but not beta7 integrin -/- mice exhibited this trait. By contrast, structures important for antigen transport (subepithelial dome and M cells) were comparable among genotypes. Similar numbers of dendritic cells were observed in the Peyer's patches and lamina propria of all genotypes of mice suggesting the use of mechanisms independent of L-selectin and beta7 integrin for their migration to mucosal tissues. Mucosal immune responses were evaluated in mutant mice following oral immunization. Interestingly, germinal center formation was poorly organized in Peyer's patches of beta7 integrin-/- and L-selectin/beta 7 integrin-/- mice despite a significant increase in the frequency of GL7+ germinal center cells in these animals. In contrast to peripheral lymphoid tissues, no increases in GL7+ cells or germinal center formation were seen in Peyer's patches or MLN of any genotype following immunization. beta7 integrin-/- mice were the most susceptible to challenge with S. typhimurium and exhibited increased mortality compared to all other genotypes. These results suggest that factors in addition to lymphocyte recirculation are required for generation of protective mucosal immune responses.