Deriving mechanisms of immune-mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by strong linkage disequilibrium. To determine whether causal variants could be identified from their functional effects, we adapted a massively parallel reporter assay for use in primary CD4 T cells, the cell type whose regulatory DNA is most enriched for immune-mediated disease SNPs. This enabled the effects of candidate SNPs to be examined in a relevant cellular context and generated testable hypotheses into disease mechanisms. To illustrate the power of this approach, we investigated a locus that has been linked to six immune-mediated diseases but cannot be fine-mapped. By studying the lead expression-modulating SNP, we uncovered an NF-κB-driven regulatory circuit which constrains T-cell activation through the dynamic formation of a super-enhancer that upregulates TNFAIP3 (A20), a key NF-κB inhibitor. In activated T cells, this feedback circuit is disrupted-and super-enhancer formation prevented-by the risk variant at the lead SNP, leading to unrestrained T-cell activation via a molecular mechanism that appears to broadly predispose to human autoimmunity.