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.
Children with Down Syndrome (DS) frequently undergo tonsillectomy for obstructive sleep apnea. Tonsils are considered secondary lymphoid tissues (SLTs), similar to lymph nodes. Our laboratory has studied the development of natural killer (NK) cells and innate immune lymphoid cells (ILCs), which occurs in the tonsils and other SLTs, but, to date, no systematic study of NK cells or ILC development (and function in the SLTs) has been performed in DS. Based on our preliminary data, we observe significant higher bacterial load in tonsils, abnormalities in both the NK and ILC3 populations, and have identified a novel NKB cell population. Collectively, these studies have considerable implications for understanding the pathology associated with DS and for developing rational treatments to prevent some of the complications that occur in people with DS.
