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NIH grant 1R01EY039451-01: A T cell intrinsic role for NOD2 in suppression of uveitis
Institute: {'code': 'EY', 'abbreviation': 'NEI', 'name': 'National Eye Institute', 'admin_org_id': '12500073', 'admin_funding_url': ''}. PI: RUTH NAPIER. Award: $706718.
Start: 2026-09-30T00:00:00.
PROJECT SUMMARY
Uveitis is a sight-threatening inflammatory disease responsible for ~10-15% of blindness in the U.S. and
worldwide. While diverse in presentation, many forms of uveitis share a common feature: dysregulated T cell
responses that damage ocular tissues. Blau syndrome, a rare monogenic inflammatory disease of the eye,
joints, and skin, results from mutations in the microbial sensor NOD2. Although originally characterized as a
gain-of-function autoinflammatory disease driven by innate immunity, Blau patients fail to respond to therapies
used for other autoinflammatory disorders, underscoring gaps in our understanding of disease mechanisms.
Our published and preliminary data reveal a previously unrecognized, T cell intrinsic function of NOD2 as a
checkpoint regulator of pathogenic Th17 cells. Specifically, NOD2 restrains TCR-driven signaling cascades
that promote IL-17A and IL-17F production. Blau patient T cells exhibit hyper-activation of proximal TCR
signaling, excessive IL-2 production, and enhanced mTORC1-driven Th17 differentiation. Consistently, Blau
knock-in mice display exacerbated experimental autoimmune uveitis (EAU), and Blau patients treated with IL-
17 inhibitors showed marked disease improvement. Together, these findings challenge the prevailing “gain-of-
function” paradigm and instead point to a loss-of-function model in which defective NOD2 signaling in T cells
drives pathogenic Th17 responses. The central hypothesis of this proposal is that NOD2 functions downstream
of the TCR to restrain mTORC1-dependent Th17 responses, and that Blau-associated mutations unleash
pathogenic IL-17A/F production that drives uveitis. To test this hypothesis, we propose three Specific Aims: (1)
Define how NOD2 restrains proximal TCR/CD28 signaling in human CD4+ T cells, (2) Determine how
mTORC1 activation promotes enhanced Th17 responses in Blau patient CD4+ T cells, (3) Establish the
contribution of T cell-derived IL-17A/F to Blau-associated uveitis using Blau KI heterozygous mice and pre-
clinical IL-17 blockade. This work will redefine Blau syndrome as a T cell-mediated disease, shifting the field
away from an innate-only model. By uncovering how NOD2 regulates T cell signaling and pathogenic IL-17
responses, these studies will provide mechanistic insight into uveitis pathogenesis and pre-clinical evidence for
IL-17-targeted therapy in Blau and potentially broader patient populations.document fetched 2026-10-11 02:50