Although prematurity and subsequent feeding are risk factors, understanding the development and function of T cells within the mucosa of the gastrointestinal tract may give insight into NEC pathophysiology. Small lymphoid aggregates are found throughout the length of the small intestine of mice, within the lamina propria, and below the epithelial crypts. We have previously shown a temporal relationship between the appearance of lymphoid aggregates and the subsequent enrichment in intraepithelial lymphocytes (IEL) coincident with the time of weaning in mice. Defects in T-cell or B-cell colonization of lymphoid aggregates may correlate with NEC pathogenesis. We therefore sought to define the cellular composition of discrete intestinal lymphoid aggregates during ontogeny. We found clusters of CD117+ cells characteristic of CP aggregates in the small intestine of specific pathogen-free wild-type mice beginning at 14 days of life. Although the CD117+ composition remained unchanged throughout adult life, B cells, which are characteristic of ILF, appeared in lymphoid aggregates at the time of weaning and increased with advancing age. By 7 to 9 weeks of age, the majority of lymphoid aggregates contained B cells. T cells were present within these lymphoid aggregates as early as 17 days, preceding the appearance of B cells. Taken together, these data suggest a phenotypic transition of lymphoid aggregates from CP to ILF. Given the dynamic composition of lymphoid aggregates during ontogeny, we hypothesized that this is an antigen-driven process. We identified M cells within the overlying epithelium of early aggregates prior to B-cell enrichment. Dendritic cells appeared shortly after initial aggregate formation and increased in number with age. Moreover, a large proportion of these dendritic cells exhibited an activated phenotype based on MHC class II and CD86 expression. Furthermore, we identified a subset of aggregate dendritic cells expressing CD11clo CD45RBhi, previously shown to induce T regulatory differentiation. We wanted to determine whether regulatory T cells were present within these lymphoid aggregates. We identified T cells expressing CD4 and CD25 consistent with a regulatory cell surface phenotype. Based on these data, we propose a role for small intestinal lymphoid aggregates as a site of localized antigen presentation and regulatory T-cell induction. Alterations in the colonization of lymphoid aggregates may have important implications in intestinal immune homeostasis. We therefore propose that alterations in the development and maturation of lymphoid aggregates contribute to the susceptibility of the premature infant to NEC.
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