Hall, J. A. | Search bioRxiv

bioRxiv2019

Serum Amyloid A Proteins Induce Pathogenic TH17 Cells and Promote Inflammatory Disease

Lymphoid cells that produce IL-17 cytokines protect barrier tissues from pathogenic microbes, but are also prominent effectors of inflammation and autoimmune disease. T-helper (TH17) cells, defined by ROR{gamma}t-dependent production of IL-17A and IL-17F, exert homeostatic functions in the gut upon microbiota-directed differentiation from naive CD4+ T cells. In the non-pathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, TH17 cell behaviors vary markedly according to their environment. Here we show that SAAs additionally direct a pathogenic pro-inflammatory TH17 cell differentiation program, acting directly on T cells in collaboration with STAT3-activating cytokines. Using loss- and gain-of-function mouse models, we show that SAA1, SAA2, and SAA3 have distinct systemic and local functions in promoting TH17-mediated inflammatory diseases. These studies suggest that T cell signaling pathways modulated by the SAAs may be attractive targets for anti-inflammatory therapies.

immunology↗

bioRxiv2018

Transcriptional regulatory networks that promote and restrict identities and functions of intestinal innate lymphoid cells

Innate lymphoid cells (ILCs) can be subdivided into several distinct cytokine-secreting lineages that promote tissue homeostasis and immune defense but also contribute to inflammatory diseases. Accumulating evidence suggests that ILCs, similarly to other immune populations, are capable of phenotypic and functional plasticity in response to infectious or environmental stimuli. Yet the transcriptional circuits that control ILC identity and function are largely unknown. Here we integrate gene expression and chromatin accessibility data to infer transcriptional regulatory networks within intestinal type 1, 2, and 3 ILCs. We predict the \"core\" sets of transcription-factor (TF) regulators driving each ILC subset identity, among which only a few TFs were previously known. To assist in the interpretation of these networks, TFs were organized into cooperative clusters, or modules that control gene programs with distinct functions. The ILC network reveals extensive alternative-lineage-gene repression, whose regulation may explain reported plasticity between ILC subsets. We validate new roles for c-MAF and BCL6 as regulators affecting the type 1 and type 3 ILC lineages. Manipulation of TF pathways identified here might provide a novel means to selectively regulate ILC effector functions to alleviate inflammatory disease or enhance host tolerance to pathogenic microbes or noxious stimuli. Our results will enable further exploration of ILC biology, while our network approach will be broadly applicable to identifying key cell state regulators in other in vivo cell populations.

immunology↗