W161 - Immune Dysregulation in Children with down Syndrome: Altered Tonsillar Architecture and Reduced Follicle Size Correlate with Increased Frequencies of CD4+ PD1int CXCR3+ T Cells and Decreased Follicular Helper T Cell Frequencies

Abstract Text: People with Trisomy 21 (T21) have distinctive susceptibility to diseases due to an early immune dysregulation. We investigated T-B cell interactions in tonsils, as a proxy of secondary lymphoid organs (SLO). We looked for the germinal center (GC) reaction, the area within follicles where mature cells undergo intense proliferation, differentiation, and selection during an immune response, with the help of follicular helper T cells (Tfh). Multiparametric flow cytometry and multiplex immunofluorescence characterized B and T cells in hypertrophied, non-infected tonsils in T21 children compared to age-matched controls (n=10). We focused on the expression of CXCR3 and other markers associated with Th1 response, inflammation and autoimmunity. The architecture and frequency of different populations from the tonsils' B and T zones were analyzed.
There was a marked remodeling of T-B cell compartments in T21 tonsils, with increased frequency of different CXCR3-expressing cells, such as memory B cells (p < 0.05), GC B cells, plasmablasts (p < 0.01) and activated non Tregs nor Tfh CXCR3+ T cells in detriment of conventional Tfh (p < 0.05). The density (#cells/mm2) of CXCR3+ Tfh-like cells outside follicles significantly increased in T21, suggesting heightened extrafollicular responses. CXCR3+ Tfh and B cells were closer together in the T zone of T21 tonsils, suggesting stronger interactions outside follicles. T21 substantially impacted the tonsil T and B cell compartments, inhibiting Tfh and GC formation while increasing CXCR3+ B cells in the T cell zone. Our results suggest that both the GC reaction and he spatial distribution of T and B cells are altered in T21 tonsils.