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- W4313430095 abstract "Abstract Human inborn errors of immunity (IEIs) are a class of genetic disorders caused by monogenic germline mutations that impair the function of the encoded protein. We recently described a novel IEI due to an IL2RB homozygous mutation (p.Pro222_Gln225Del) in two siblings who suffered from multi-organ autoimmunity and CMV susceptibility. This mutation resulted in decreased cell surface protein expression and increased serum IL-2/15 levels, with concomitant increased baseline STAT5 phosphorylation (pSTAT5) but poor pSTAT5 response to IL-2 and IL-15 stimulation. Counterintuitively, this IL-2Rβ hypomorphic mutation led to an expansion of memory CD8+ T and immature CD56bright NK cells, which express the highest levels of IL-2Rβ and require IL-2/15 signaling for survival and differentiation. Yet, their maturation and function appeared impaired, suggesting that both intrinsic (hypomorphic receptor) and extrinsic (serum cytokine milieu) mechanisms were at play. To further interrogate these receptor instrinsic/extrinsic mechanisms we developed a mouse model that harbors the homolog mutation (Il2rbMut/Mut). When mutant bone marrow cells reconstituted a WT host, serum IL-2/15 levels and IL-2Rβ protein surface expression partially normalized, though IL-2/15-induced signaling remained hypofunctional. Additionally, the dysregulated mutant IL-2Rβ-driven CD8+ T cell immunophenotype normalized but the NK phenotype did not. These data highlight the asymmetrical effect that a partial IL-2Rβ defect has on CD8 T and NK cell IL-2/15-dependent signaling and downstream cellular processes. These results imply that strategies to modify serum IL-2/15 levels may serve as a therapeutic approach to treating IL-2/15 signaling defects. Supported by grants from NIH (T32 AI074491, K23 AR070897)" @default.
- W4313430095 created "2023-01-06" @default.
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- W4313430095 date "2022-05-01" @default.
- W4313430095 modified "2023-09-26" @default.
- W4313430095 title "Dissecting the effect of a novel hypomorphic <i>IL2RB</i> mutation on immune dysregulation." @default.
- W4313430095 doi "https://doi.org/10.4049/jimmunol.208.supp.159.08" @default.
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