NIH grant: Encephalitogenic stem-like T cells in MS and its disease models (1R56AI190188-01A1)

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NIH grant 1R56AI190188-01A1: Encephalitogenic stem-like T cells in MS and its disease models
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Daniel  Hawiger. Award: $657288.
Start: 2026-08-07T00:00:00.
Despite currently available therapeutic approaches, multiple sclerosis (MS) remains an incurable disease.
Studies in MS patients and corresponding animal models show that encephalitogenic T effector cells (TEFF)
promote key autoimmune responses during MS pathogenesis. Within the central nervous system (CNS) of MS
patients, these autoimmune T cells infiltrate the brain and then circulate back into the peripheral immune system,
where they are maintained and reactivated, making such T cells a feasible diagnostic and therapeutic target.
The mechanisms responsible for the maintenance of the encephalitogenic TEFF repertoire remain unclear. Stem-
like T cells (TSTEM) that continue to differentiate into TEFF were proposed to contribute to the onset and
exacerbation of human MS and its animal models. However, gaps in knowledge about the molecular
characteristics of these encephalitogenic T cells and technical limitations severely hamper such advances. To
overcome these limitations, we have developed a novel, state-of-the-art analytical tool, Seqtometry (sequencing-
to-measurement), for analyzing single-cell sequencing data. As presented in this proposal, we performed an in-
depth transcriptomic analysis of encephalitogenic T cells from the CNS and peripheral blood of MS patients and
successfully identified MS-linked TSTEM, which were conspicuously absent in healthy or MS-free controls. We
confirmed our findings using T cells specific for myelin oligodendrocyte glycoprotein (MOG), a relevant neuronal
antigen, in an animal model of MS. Our most recent studies identified CD4+ T cells programmed for differentiation
into TEFF with specific transcriptomic signature profiles corresponding to the MS-linked TSTEM, highlighting the
conservation of encephalitogenic TSTEM. Based on these significant findings, we hypothesize that key
transcriptomic characteristics that are conserved in T cells from MS patients and relevant animal models can
foretell the early disease process and offer insights into the molecular mechanisms that govern the
encephalitogenic differentiation of autoimmune T cells. Our further studies revealed in encephalitogenic TSTEM
specific molecular mechanisms dependent on the homeodomain-only protein (Hopx) that governs effector
differentiation of these cells. We additionally hypothesize that intrinsic mechanisms of Hopx in TSTEM orchestrate
key pro-encephalitogenic functions. We will test our hypotheses in three aims: In Aim 1, we will determine the
trajectories of encephalitogenic differentiation, In Aim 2, we will reveal the molecular mechanisms orchestrating
fate and functions of TSTEM and clarify functions of Hopx, In Aim 3, we will determine the molecular characteristics
of MS-linked TSTEM. Overall, the expected results of this research would provide us with key insights into
molecular mechanisms underlying differentiation of encephalitogenic T cells, also helping to usher us into
developing new MS diagnostic tools.

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