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The ADP-Ribosylation Factor 4d Restricts Regulatory T-Cell Induction via Control of IL-2 Availability

Interleukin-2 is central to the induction and maintenance of both natural (nT(reg)) and induced Foxp3-expressing regulatory T cells (iT(reg)). Thus, signals that modulate IL-2 availability may, in turn, also influence T(reg) homeostasis. Using global knockout and cell-specific knockout mouse models,...

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Detalles Bibliográficos
Autores principales: Geers, Bernd, Hagenstein, Julia, Endig, Jessica, Ulrich, Hanna, Fleig, Laura, Sprezyna, Paulina, Mikulec, Julita, Heukamp, Lukas, Tiegs, Gisa, Diehl, Linda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454872/
https://www.ncbi.nlm.nih.gov/pubmed/36078047
http://dx.doi.org/10.3390/cells11172639
Descripción
Sumario:Interleukin-2 is central to the induction and maintenance of both natural (nT(reg)) and induced Foxp3-expressing regulatory T cells (iT(reg)). Thus, signals that modulate IL-2 availability may, in turn, also influence T(reg) homeostasis. Using global knockout and cell-specific knockout mouse models, we evaluated the role of the small GTPase ADP-ribosylation factor 4d (Arl4d) in regulatory T-cell biology. We show that the expression of Arl4d in T cells restricts both IL-2 production and responsiveness to IL-2, as measured by the phosphorylation of STAT5. Arl4d-deficient CD4 T cells converted more efficiently into Foxp3(+) iT(reg) in vitro in the presence of αCD3ε and TGFβ, which was associated with their enhanced IL-2 secretion. As such, Arl4d(−/−) CD4 T cells induced significantly less colonic inflammation and lymphocytic infiltration in a model of transfer colitis. Thus, our data reveal a negative regulatory role for Arl4d in CD4 T-cell biology, limiting iT(reg) conversion via the restriction of IL-2 production, leading to reduced induction of T(reg) from conventional CD4 T cells.