Summary The differentiation of CD4+ helper T cell subsets with diverse effector functions is accompanied by changes in metabolism required to meet their bioenergetic demands. We find follicular B helper T (Tfh) cells exhibited less proliferation, glycolysis, and mitochondrial respiration, accompanied by reduced mTOR kinase activity compared to T helper 1 (Th1) cells in response to acute viral infection. IL-2-mediated activation of the Akt kinase and mTORc1 signaling was both necessary and sufficient to shift differentiation away from Tfh cells, instead promoting that of Th1 cells. These findings were not the result of generalized signaling attenuation in Tfh cells, as they retained the ability to flux calcium and activate NFAT transcription factor-dependent cytokine production. These data identify the interleukin-2 (IL-2)-mTORc1 axis as a critical orchestrator of the reciprocal balance between Tfh and Th1 cell fates and their respective metabolic activities following acute viral infection.

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Genome-wide association studies have now identified tens of thousands of noncoding loci associated with human diseases and complex traits, each of which could reveal insights into biological mechanisms of disease. Many of the underlying causal variants are thought to affect enhancers, but we have lacked genome-wide maps of enhancer-gene regulation to interpret such variants. We previously developed the Activity-by-Contact (ABC) Model to predict enhancer-gene connections and demonstrated that it can accurately predict the results of CRISPR perturbations across several cell types. Here, we apply this ABC Model to create enhancer-gene maps in 131 cell types and tissues, and use these maps to interpret the functions of fine-mapped GWAS variants. For inflammatory bowel disease (IBD), causal variants are >20-fold enriched in enhancers in particular cell types, and ABC outperforms other regulatory methods at connecting noncoding variants to target genes. Across 72 diseases and complex traits, ABC links 5,036 GWAS signals to 2,249 unique genes, including a class of 577 genes that appear to influence multiple phenotypes via variants in enhancers that act in different cell types. Guided by these variant-to-function maps, we show that an enhancer containing an IBD risk variant regulates the expression of PPIF to tune mitochondrial membrane potential. Together, our study reveals insights into principles of genome regulation, illuminates mechanisms that influence IBD, and demonstrates a generalizable strategy to connect common disease risk variants to their molecular and cellular functions.

Summary Regulatory T (Treg) cells require PTEN to block PI3K signaling while maintaining Foxp3 expression. In the absence of PTEN, Treg cells lose Foxp3 expression and their suppressive function, leading to a systemic increase in interferon-γ secretion, with consequent expansion of pathogenic T helper 1 and follicular B helper T cells and systemic autoimmunity.

Pooled CRISPR screens allow high-throughput interrogation of genetic elements that alter expression of a reporter gene readout. New computational methods are needed to model these data. We created MAUDE (Mean Alterations Using Discrete Expression) for quantifying the impact of guide RNAs on a target gene's expression in a pooled, sortingbased expression screen. MAUDE quantifies guide-level effects by modeling the distribution of cells across sorting expression bins. It then combines guides to estimate the statistical significance and effect size of targeted genetic elements. We show that MAUDE significantly improves over previous approaches and provide experimental design guidelines to best leverage MAUDE.