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Summary Atg16L1 mediates the cellular degradative process of autophagy and is considered a critical regulator of inflammation based on its genetic association with inflammatory bowel disease. Here we find that Atg16L1 deficiency leads to an exacerbated graft-versus-host disease (GVHD) in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Atg16L1-deficient allo-HSCT recipients with GVHD displayed increased T cell proliferation due to increased dendritic cell (DC) numbers and costimulatory molecule expression. Reduced autophagy within DCs was associated with lysosomal abnormalities and decreased amounts of A20, a negative regulator of DC activation. These results broaden the function of Atg16L1 and the autophagy pathway to include a role in limiting a DC-mediated response during inflammatory disease, such as GVHD. [ABSTRACT FROM AUTHOR]

The clinical benefit of T cell immunotherapies remains limited by incomplete understanding of T cell differentiation and dysfunction. We generated an epigenetic and transcriptional atlas of T cell differentiation from healthy humans that included exhausted CD8 T cells and applied this resource in three ways. First, we identified modules of gene expression and chromatin accessibility, revealing molecular coordination of differentiation after activation and between central memory and effector memory. Second, we applied this healthy molecular framework to three settings—a neoadjuvant anti-PD1 melanoma trial, a basal cell carcinoma scATAC-seq dataset, and autoimmune disease-associated SNPs—yielding insights into disease-specific biology. Third, we predicted genome-wide cis -regulatory elements and validated this approach for key effector genes using CRISPR interference, providing functional annotation and demonstrating the ability to identify targets for non-coding cellular engineering. These studies define epigenetic and transcriptional regulation of human T cells and illustrate the utility of interrogating disease in the context of a healthy T cell atlas. • RNA-seq and ATAC-seq atlas of 14 human T cell subsets from healthy donors • The atlas provides a reference map for interpreting signatures of T cells from 3 diseases • Prediction of cis -regulatory elements that control CD8 T cell subset gene expression • Validation of functional enhancers for CXCR3 and GZMB using CRISPRi Giles et al. generated an epigenomic T cell differentiation atlas from healthy human donor (HD) blood. This atlas was used to (1) identify transcriptional and epigenetic modules in human CD8 T cell differentiation, (2) interpret signatures of T cells from cancer and autoimmunity, and (3) predict and validate CD8 T cell enhancers. [ABSTRACT FROM AUTHOR]

CD8+ T cell exhaustion is a major barrier to current anti-cancer immunotherapies. Despite this, the developmental biology of exhausted CD8+ T cells (Tex) remains poorly defined, restraining improvement of strategies aimed at "re-invigorating" Tex cells. Here, we defined a four-cell-stage developmental framework for Tex cells. Two TCF1+ progenitor subsets were identified, one tissue restricted and quiescent and one more blood accessible, that gradually lost TCF1 as it divided and converted to a third intermediate Tex subset. This intermediate subset re-engaged some effector biology and increased upon PD-L1 blockade but ultimately converted into a fourth, terminally exhausted subset. By using transcriptional and epigenetic analyses, we identified the control mechanisms underlying subset transitions and defined a key interplay between TCF1, T-bet, and Tox in the process. These data reveal a four-stage developmental hierarchy for Tex cells and define the molecular, transcriptional, and epigenetic mechanisms that could provide opportunities to improve cancer immunotherapy. • Ly108 and CD69 define four Tex subsets linked in a hierarchical developmental pathway • Two TCF1+ subsets, effector-like and terminally exhausted subsets, are identified • Key transcriptional, epigenetic, and biological changes define subset transitions • TCF1, T-bet, and Tox coordinate Tex subset development and dynamics Beltra et al. define a hierarchical developmental pathway for CD8+ T cell exhaustion, revealing four stages and multistep transcriptional and epigenetic dynamics underlying subset transitions and subset-associated biological changes. [ABSTRACT FROM AUTHOR]