Autoimmunity

Defective Aire-dependent central tolerance to myelin protein zero is linked to autoimmune peripheral neuropathy

Aire deficiency predisposes to peripheral nervous system (PNS) autoimmunity. We identified myelin protein zero (MPZ or P0) as a PNS-specific Aire-regulated antigen expressed in the thymus. Aire deficiency allows escape of P0-specific T cells to escape negative selection to cause PNS autoimmunity. We discovered that autoimmune-prone NOD mice with a dominant Aire G228W mutation develop spontaneous PNS autoimmunity that resembles features of Guillain-Barré Syndrome and its chronic counterpart, chronic inflammatory demyelinating polyneuropathy (CIDP) (Su et al, J Immunol, 2012). APS1 patients have also been reported to develop CIDP, suggesting that Aire deficiency also predisposes to PNS autoimmunity in humans. See our review on CIDP pathogenesis: Wolbert et al, JCI Insight, 2020

Graphical abstract illustrating how deletion of autoimmune regulator prevents antigen presentation of myelin protein zero during negative selection of T cell development. As a result, autoreactive T cells escape the thymus and cause damage to the peripheral nerves.
Schematic representation of tolerance mechanisms important in preventing PNS autoimmunity and pathogenic mechanisms that lead to CIDP. In a physiologically healthy state, P0-reactive T cells undergo negative selection. In the thymus, AIRE controls expression of tissue-specific antigens, such as P0, and recognition of these antigens by developing T cells leads to their negative selection. In CIDP, loss of negative selection by decreased AIRE results in escape of autoreactive T cells into the periphery. Peripheral tolerance mechanisms, including immunosuppressive Treg activity, have also been implicated in preventing PNS autoimmunity. 

A pathologically expanded, clonal lineage of IL-21–producing CD4+ T cells drives inflammatory neuropathy

Among T cells, CD4+ T cells in particular are critical in the pathogenesis of inflammatory neuropathies. CD4+ T cells are increased in peripheral nerves of patients with inflammatory neuropathies and SAPP mouse models, suggesting a role for CD4+ T cells in peripheral nerve myelin destruction. We showed that, in peripheral nerve infiltrates of neuropathic Aire-deficient NOD mice, terminally differentiated effector CD4+ T cells were clonally expanded and expressed IL-21. These IL-21–producing cells could be grouped into 2 transcriptionally distinct populations, which resembled T follicular helper (Tfh) and T peripheral helper (Tph) cells. Notably, TCR clonotypes were shared in these 2 subsets, supporting the idea of a common lineage for these 2 cell populations. Additionally, we demonstrate that IL-21 signaling was required for neuropathy development and that IL-21 upregulated CXCR6, a chemokine that promotes CD4+ T cell localization within peripheral nerves. Read the paper: Seyedsadr et al, JCI, 2024

Schematic representation of a model of inflammatory neuropathy whereby CD4+ T follicular and peripheral helper cells produce proinflammatory cytokine IL-21. IL-21 signaling upregulates CXCR6 in T peripheral helper cells, a chemokine receptor that promotes T cell localization in the peripheral nerves.
In peripheral nerve infiltrates of neuropathic NOD.AireGW/+ mice, terminally differentiated effector CD4+ T cells are clonally expanded and express IL-21. These IL-21–producing cells can be grouped into two transcriptionally distinct populations, which resemble T follicular helper (Tfh) and T peripheral helper (Tph) cells. IL-21 signaling is required for neuropathy development and IL-21 upregulates CXCR6, a chemokine that promotes CD4+ T cell localization within peripheral nerves. Together, our findings demonstrate a critical role for IL-21 in disease pathogenesis and reveal multiple new molecular targets for the treatment of autoimmune peripheral neuropathies.

Pathologic T cell immunosenescence drives the development of age-associated autoimmune peripheral neuropathy

While certain autoimmune conditions occur commonly in the young, others are more frequent in the aged. A striking example is chronic inflammatory demyelinating polyneuropathy (CIDP), an autoimmune disease of peripheral nerves that occurs at a peak decade of onset of 70-79 years. How aging predisposes to autoimmunity, however, remains unclear. In CIDP patients, we identified an expanded population of T cells that exhibit hallmark senescence features, including increased SA-βGal activity and higher CDKN1A expression. These senescence associated T cells express multiple senescence associated secretory phenotype (SASP) factors (IFN-γ, TNF-α, TGF-β, IL21, Spp1) and demonstrated an enhanced capacity for inciting neuropathy in a CIDP mouse model. Notably, SASP suppression by a clinically available senomorphic therapy dampened senescence features in peripheral nerves and protected mice against neuropathy. Together, these findings delineate a key role for T cells exhibiting a pro-inflammatory SASP in predisposing to age-associated autoimmune disease. Read the preprint: McCarthy et al, Biorxiv, 2026

Schematic representation of a model of age-associated inflammatory neuropathy whereby a pathologic senescent CD4+ T cell population exhibits increased capacity for PNS autoimmunity. Senomorphic therapy ruxolitinib ameliorates disease by suppression of senescent features.
In patients with CIDP, we identified an expanded population of T cells that exhibit senescence associated features, including increased SA-βGal activity and enhanced CDKN1A (p21) expression. These senescent T cells also acquire a pro-inflammatory senescence-associated secretory phenotype (SASP), which is characterized by dysregulated secretion of multiple pro-inflammatory factors (e.g., IFN-γ, TNF-α, TGF-β, SPP1/OPN, IL-10, IL-21). These senescence-associated T cells (SATs) accumulate in infiltrated peripheral nerves of a CIDP mouse model and induced neuropathy more readily in immunodeficient hosts. Importantly, a senescence-modifying therapy protects against autoimmune peripheral neuropathy through the inhibition of SASP factor production and dampening of senescence features in peripheral nerve cells. These findings point to the deployment of senotherapies as a class of medications that may be effective in the treatment of CIDP and other aging-associated autoimmune diseases.

UTX coordinates TCF1 and STAT3 to control progenitor CD8+ T cell fate in autoimmune diabetes

Type 1 diabetes mellitus (T1D) is a chronic disease caused by an unremitting autoimmune attack on pancreatic β cells. This autoimmune chronicity is mediated by stem-like progenitor CD8+ T cells that continually repopulate the pool of β cell–specific cytolytic effectors. Factors governing the conversion of progenitors to effectors, however, remain unclear. T1D has been linked to a chromosomal region (Xp13-p11) that contains the epigenetic regulator UTX, which suggests a key role for UTX in T1D pathogenesis. Here, we show that T cell–specific UTX deletion in NOD mice protects against T1D development. In T cells of NOD mice and patients with T1D, UTX ablation resulted in the accumulation of CD8+ progenitor cells with a concomitant decrease of effector cells, suggesting a key role for UTX in poising progenitors for transition to effectors. Mechanistically, UTX’s role in T1D was independent of its inherent histone demethylase activity but instead relied on binding with transcription factors (TCF1 and STAT3) to coregulate genes important in the maintenance and differentiation of progenitor CD8+ T cells. Read the paper: Chen et al, JCI, 2025

Schematic representation depicting a model of type 1 diabetes mellitus whereby stem-like progenitor CD8+ T cells differentiate into beta cell-specific cytolytic effectors. Histone demethylase UTX promotes this T cell differentiation program by coordinating transcription factors TCF1 and STAT3.
T cell–specific UTX expression was required for T1D through its role in driving stem-like progenitor T (Tprog) cells to become cytolytic effector T (Teff) cells. This role was independent of its demethylase function but instead involved cooperative interactions between UTX and the transcription factors TCF1 and STAT3. UTX, TCF1, and STAT3 co-occupancy at key progenitor and effector gene loci enforces a transcriptional program that drives Tprog to Teff conversion. These findings point to UTX as a critical regulator of the T1D autoimmune response and point to targeting UTX:TCF1:STAT3 mechanisms as a potential approach for interrupting the persistent autoimmune attack.