Persistent exposure to endogenous LPS programs colonic lamina propria dendritic cells to impair CD4+Th17 immunity in vivo

Abstract Gram-negative bacteria drive CD4+ T helper type-17 (Th17) immunity via lipopolysaccharide (LPS) activation of Toll-like receptor (TLR)4. However, excessive TLR4 stimulation can lead to a period of LPS tolerance, during which antigen-presenting cells (APCs) become non-responsive to LPS. Acyloxyacyl hydrolase (AOAH) is a host enzyme mainly expressed by APCs that inactivates LPS, preventing LPS tolerance. Since the effects of AOAH function on T cell immunity remains unexplored, we sought to investigate whether AOAH deficiency modulates the ability of dendritic cells (DCs) to generate CD4+ T cell immunity. We demonstrate that DCs isolated from the colonic lamina propria (cLP), specifically the CD103+CD11b+ subset, exhibited high functional levels of AOAH and preferentially polarized Ag-specific Th17 immunity. The absence of TLR4, or the depletion of gram-negative flora, diminished the ability of cLP DCs to express AOAH and promote Ag-specific Th17 immunity. AOAH-deficient cLP DCs reduced the generation of Ag-specific Th17 cells ex vivo and in vivo, while increasing CD4+ T regulatory cell production. These data demonstrate that AOAH deficiency, which increases exposure to LPS, conditions cLP DCs to impair Ag-specific Th17 immunity. Furthermore, these results show that host pathways to handle microflora-derived products can influence T cell polarization, and suggest that these pathways may be involved in susceptibility to infectious and immune-mediated diseases.