Selective JAK Inhibition Reveals Paradoxical and Hierarchical Control of interferon-γ-driven Autoimmunity in AIRE...

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by impaired central immune tolerance due to deficiency of the Autoimmune Regulator (AIRE) and is characterized by severe, multiorgan autoimmunity. We recently identified interferon-γ (IFN-γ) as a dominant driver of immunopathology in APECED and showed that treatment with the JAK1/2 inhibitor ruxolitinib ameliorates disease in both AIRE-deficient mice and patients. However, broad JAK inhibition is associated with clinically relevant toxicities, raising the question of whether selective targeting of individual JAK pathways can retain efficacy while sparing nonpathogenic immune programs. Here, we systematically evaluated the effects of selective JAK1, JAK2, and JAK3 inhibition in Aire^-/- mice. Selective JAK1 and JAK2 inhibition reduced autoimmune tissue injury, suppressed IFN-γ signaling, and decreased accumulation of pathogenic T cells, with JAK2 inhibition providing the most robust protection, comparable to ruxolitinib. In contrast, selective JAK3 inhibition decreased T cell accumulation, but paradoxically increased the proportion of IFN-γ-producing T cells and did not significantly attenuate IFN-γ-driven tissue inflammation. These findings reveal an unexpected uncoupling between lymphocyte burden and pathogenic cytokine bias and identify IFN-γ signaling as hierarchically dominant over γc-dependent pathways in AIRE deficiency. Together, our data indicate that effective control of APECED-associated autoimmunity requires direct suppression of the IFN-γ-JAK2 axis rather than generalized lymphocyte inhibition and suggest that selective JAK2 targeting may represent a rational strategy to preserve therapeutic efficacy while minimizing disruption of JAK1- and γc-dependent immune functions.