The Regulation of Type 3 ILC and γδ T Cell Plasticity

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2022

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Abstract

Lymphocytes take on effector programs coordinated by lineage-defining transcription factors (LDTF), resulting in the production of cytokines that fight specific types of pathogens. Therefore, both adaptive and innate lymphocyte lineages can take on specialized effector programs; the type 1 program mediated by T-bet for killing intracellular pathogens and tumors, the type 2 program controlled by GATA3 for protection against helminths, and the type 3 program mediated by RORγt for fighting extracellular bacteria and fungi. While each program can be defined by a single LDTF, many context-dependent situations arise that lead to more than one LDTF being expressed in a cell at a given time. The dual expression of LDTFs can result in the switching of effector programs within a differentiated cell. Nevertheless, LDTFs work in a cooperative manner with signal-dependent TFs and other TFs that sense environmental cues to ultimately control effector fates.

Environmental signals can be sensed by various classes of cell-surface receptors that modulate the downstream signaling effectors and subsequent transcriptional output of a cell for differentiation, proliferation, maintenance, and effector function. Surface receptors, such as the T cell receptor (TCR), cytokine receptors, and costimulatory receptors, translate the environmental cues into downstream signaling cascades that act in concert to promote the differentiation of lymphocyte subsets. Cytokines fine-tune the activation and repression of lymphocytes through phosphorylation of signal transducer and activator of transcription (STAT) TFs that translocate into the nucleus, bind DNA, and regulate gene expression at key loci. Acting alongside STAT TFs, AP-1 TFs are basic leucine zipper (bZIP) TFs that help translate environmental cues into effector programming through binding to key TF and effector cytokine loci.

The ability of a differentiated cell to switch to an alternative fate is referred to as plasticity. Innate lymphoid cells (ILCs) are remarkably plastic at steady state and fate-mapping studies in the mouse intestine revealed that RORγt+ ILCs (ILC3s) can upregulate T-bet and shut down RORγt expression for full conversion to a type 1 ILC (ILC1). ILC3s help maintain healthy mucosal barriers through the production of IL-22 that promotes the release of antimicrobial peptides from epithelial cells. ILC3 to ILC1 plasticity therefore results in a shift from IL-22 to IFNγ production. While increased IFNγ production can be protective against viruses and intracellular pathogens, it can result in many autoimmune and inflammatory diseases when dysregulated. Notably, ILC3 plasticity is implicated in Crohn's disease.

Although the environmental cues regulating ILC3 plasticity were somewhat known, the molecular mechanisms governing ILC3 plasticity were undefined. Here, we identified the AP-1 TF c-Maf as an essential regulator of ILC3 homeostasis and plasticity that limits physiological ILC1 conversion. Phenotypic analysis of effector status in Maf-deficient CCR6- ILC3s using flow cytometry revealed a skewing towards T-bet and IFNγ production. To determine the molecular mechanisms by which c-Maf supported the type 3 program, we evaluated the global changes in transcriptome (RNA-seq), chromatin accessibility (ATAC-seq), and transcription factor motif enrichment. We found that c-Maf promoted ILC3 accessibility and supported RORγt activity and expression of type 3 effector genes. Conversely, c-Maf restrained T-bet expression and function, thereby antagonizing the type 1 program. We performed ATAC-seq on transitioning subsets in the CCR6- ILC3 compartment all the way through conversion to ILC1s to understand the chromatin landscape changes taking place during ILC3 plasticity. These results solidified c-Maf as a gatekeeper of type 1 regulatory transformation and a controller of ILC3 fate.

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Parker, Morgan E (2022). The Regulation of Type 3 ILC and γδ T Cell Plasticity. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/25270.

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