Biology subjects

Sansom, D.

Publications and source records attributed to Sansom, D..

4 recordsLinked to original sources

bioRxiv2024

Rigid, bivalent CTLA-4 binding to CD80 is required to disrupt the cis CD80 / PD-L1 interaction

The CTLA-4 and PD-1 checkpoints control immune responses to self-antigens and are key targets in cancer immunotherapy. Both pathways are connected via a cis interaction between CD80 and PD-L1, the ligands for CTLA-4 and PD-1 respectively. This cis interaction prevents PD-1 binding to PD-L1 but is reversed by CTLA-4 trans-endocytosis of CD80. However, the mechanism by which CTLA-4 selectively removes CD80 but not PD-L1 is unclear. Here we show that CTLA-4 - CD80 interactions are unimpeded by PD-L1 and that CTLA-4 binding with CD80 does not displace PD-L1 per se. Rather, both the rigidity and bivalency of the WT CTLA-4 molecule is required to orientate CD80 such that PD-L1 interactions are no longer permissible. Moreover, soluble CTLA-4 released PD-L1 only at specific expression levels of CD80 and PD-L1, whereas CTLA-4 trans-endocytosis released PD-L1 in all conditions. These data show that PD-L1 release from CD80 is driven by biophysical factors associated with orientation and bivalent cross-linking of proteins in the cell membrane and that trans-endocytosis of CD80 efficiently promotes PD-L1 availability.

immunology↗

bioRxiv2024

Lack of phosphatidylinositol 3-kinase VPS34 in regulatory T cells leads to a fatal lymphoproliferative disorder without affecting their development

Regulatory T (Treg) cells are essential for the maintenance of immunological tolerance, yet the molecular components required for their maintenance and effector functions remain incompletely defined. Inactivation of VPS34 in Treg cells led to an early, lethal phenotype, with massive effector T cell activation and inflammation, like mice lacking Treg cells completely. However, VPS34-deficient Treg cells developed normally, populated the peripheral lymphoid organs and effectively supressed conventional T cells in vitro. Our data suggest that VPS34 is required for the maturation of Treg cells or that mature Treg cells depend on VPS34 for survival. Functionally, we observed that lack of VPS34 activity impairs cargo processing upon transendocytosis, that defective autophagy contributes to, but is not sufficient to explain this lethal phenotype, and that loss of VPS34 activity induces a state of heightened metabolic activity that may interfere with metabolic networks required for maintenance or suppressive functions of Treg cells.

immunology↗

bioRxiv2023

An IL-2 mutein increases IL-10 and CTLA-4-dependent suppression of dendritic cells by regulatory T cells

Interleukin-2 (IL-2) variants with increased CD25 dependence that selectively expand Foxp3+ regulatory T (TR) cells are in clinical trials for treating inflammatory diseases. Using an Fc-fused IL-2 mutein (Fc.IL-2 mutein) we developed that prevents diabetes in non-obese diabetic (NOD) mice, we show that Fc.IL-2 mutein induced an activated TR population with elevated proliferation, a transcriptional program associated with Stat5- and TCR-dependent gene modules, and high IL-10 and CTLA-4 expression. Increased IL-10 signaling limited surface MHC class II upregulation during conventional dendritic cell (cDC) maturation, while increased CTLA-4-dependent transendocytosis led to the transfer of CD80 and CD86 costimulatory ligands from maturing cDCs to TR cells. In NOD mice, Fc.IL-2 mutein treatment promoted the suppression of cDCs in the inflamed pancreas and pancreatic lymph nodes resulting in T cell anergy. Thus, IL-2 mutein-expanded TR cells have enhanced functional properties and restrict cDC function, offering promise for targeted immunotherapy use in autoimmune disease.

immunology↗

bioRxiv2022

CTLA-4 regulates PD-L1-PD-1 interactions via transendocytosis of CD80

CTLA-4 and PD-1 are key immune checkpoints that are targeted in the treatment of cancer. Recently it has emerged that there is a physical interaction between the ligands of these pathways (CD80 and PD-L1), which can prevent PD-L1 inhibitory functions. Since CTLA-4 captures and degrades its ligands via transendocytosis, we investigated how transendocytosis of CD80 is impacted by PD-L1 interaction. We find that transendocytosis of CD80 results in a time-dependent recovery of PD-L1 availability that correlates with CD80 removal. Moreover, CD80 transendocytosis is highly specific in that only CD80 is removed, and its heterodimeric PD-L1 partner remains on the APC. We found no evidence that CTLA-4 interactions with CD80 were inhibited by PD-L1, however efficient removal of CD80 required an intact CTLA-4 cytoplasmic domain, distinguishing this process from more general trogocytosis. We also show that simple binding of CTLA-4 to the CD80-PD-L1 heterodimer is insufficient to liberate PD-L1-PD-1 interactions, suggesting that transendocytosis of CD80 is required to effectively control PD-L1-PD-1 interactions.

immunology↗