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

Abstract

Interleukin-2 is central to the induction and maintenance of both natural (nTreg) and induced Foxp3-expressing regulatory T cells (iTreg). Thus, signals that modulate IL-2 availability may, in turn, also influence Treg 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+ iTreg 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 iTreg conversion via the restriction of IL-2 production, leading to reduced induction of Treg from conventional CD4 T cells.

Mapping the global interactome of the ARF family reveals spatial organization in cellular signaling pathways

“…Pathway enrichment analyses of individual clusters revealed previously unknown localizations and functions for several ARLs. In particular, cluster 5 exhibits enrichment in preys specifically identified with ARL4D, recognized for its involvement in multiple cellular processes such as actin remodeling ( Li et al, 2007 ), neurite formation ( Yamauchi et al, 2009 ), adipogenesis ( Yu et al, 2011 ), microtubule growth ( Lin et al, 2020 ) and immune functions ( Geers et al, 2022 ; Tolksdorf et al, 2018 ). Overrepresentation analyses of Gene Ontology (GO) ‘biological processes’ (BP) are consistent with ARL4D residency in the nucleus, suggesting potential functions in the nucleolus.…”

Mapping the global interactome of the ARF family reveals spatial organization in cellular signaling pathways

“…Pathway enrichment analyses of individual clusters provide previously unknown localizations and functions for several ARFs. Cluster 5 is enriched in preys specifically identified with ARL4D, a GTPase known for its roles in actin remodeling (Li et al, 2007), neurite formation (Yamauchi et al, 2009), adipogenesis (Yu et al, 2011), microtubule growth (Lin et al, 2020), and immune functions (Geers et al, 2022) (Tolksdorf et al, 2018). Overrepresentation analyses of Gene ontology biological processes (GO BP) are consistent with ARL4D residency in the nucleus and potential functions in the nucleolus, but also reveals roles in ribosome biogenesis, regulation of RNA splicing, regulation of transcription, nucleosome organization, regulation of macromolecules biosynthetic process and RNA processing and modification (Fig.…”

“…Pathway enrichment analyses of individual clusters revealed previously unknown localizations and functions for several ARLs. In particular, cluster 5 exhibits enrichment in preys specifically identified with ARL4D, recognized for its involvement in multiple cellular processes such as actin remodeling (Li et al, 2007), neurite formation (Yamauchi et al, 2009), adipogenesis (Yu et al, 2011), microtubule growth (Lin et al, 2020), and immune functions (Geers et al, 2022, Tolksdorf et al, 2018). Overrepresentation analyses of Gene Ontology “biological processes” are consistent with ARL4D’s residency in the nucleus, suggesting potential functions in the nucleolus.…”