PROJECT ABSTRACT People with Down syndrome (DS) are more likely to develop pulmonary infections compared to disomic individuals. While the etiology of the infections in T21 individuals is almost certainly multifactorial, we have begun examining the tonsils from T21 and D21 children undergoing tonsillectomy for obstructive sleep apnea. Tonsils are considered secondary lymphoid tissues (SLTs) and within these tissues, unique tissue-resident cell populations exist. Recent studies have demonstrated that SLTs are also the site of natural killer (NK) cell and innate lymphoid cell (ILC) development. Our preliminary data show dramatic differences in T21 vs. D21 tonsils. For instance, we find lower numbers of hematopoietic (CD45+) cells in the tonsils of age matched T21 individuals. Likewise, there are higher bacterial loads in T21 (again, all tonsils were removed for obstructive sleep apnea and not tonsillitis). We also note dramatic perturbations in the ratios of NK cells and ILCs, with T21 individuals having higher proportions of NKs and fewer ILC3s. Given the role of ILC3s in mucosal integrity, these findings may account for the elevations in bacterial loads. Lastly, we have identified a rare population of cells, previously described mainly in murine models, as NKB cells which have characteristics of both NK cells and B cells. In mice, these cells respond to bacterial challenge by producing cytokines that activate NK cells. Over the course of three separate, but highly inter-related specific aims, we will address how the triplication of the four interferon receptors (FNAR1, IFNAR2, IFNGR2 & IL-10RB, all present on chromosome 21) may account for the above differences in T21 vs. D21 SLTs. As well, this data leads to a model where excessive IFN signaling reduces ILC3 cell numbers, which in turn leads to a lack of mucosal integrity and higher bacterial colonization which further drives immune activation, including the increase in the proportion of the novel NKB population.