Date: Sunday, October 21, 2018
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
In systemic lupus erythematosus (SLE), the dysregulated production of autoantibodies is a consequence of disrupted T cell homeostasis. Programmed death-1 (PD-1), a negative regulator in T cells, limits certain T cell-mediated immune responses. Increased PD-1 expression on T cells inhibits cell activation and proliferation and its blockade reinstates immune cell function. Our laboratory has shown that attenuated, but not absent, PD-1 signaling enables CD4+ regulatory T cells (Treg) to survive and suppress helper T cells Th and B cells. Gene array data have shown that attenuated PD-1 expression in Treg down-regulates several members of the TNF receptor family, including OX40L. It has been reported that OX40L is up-regulated in immune cells from patients with autoimmune disease by promoting follicular helper and effector memory T cells, and suppressing Treg proliferation. We hypothesize that one mechanism by which PD-1 sustains Treg proliferation and suppressive function is by reducing OX40L expression on Treg.
We treated lupus-prone BWF1 mice with a neutralizing Ab against PD-1 or control isotype-matched IgG intraperitoneally. OX40L, Foxp3 and PD-1 expression on Treg from the spleens was measured by flow cytometry. Treg were cocultured with unmanipulated CD4+CD25– Th and B cells, and cell proliferation/apoptosis of Treg, Th and B cells was measured with CFSE/Annexin V by flow cytometry. Cytokine production namely IFNγ (Th1), IL-4 (Th2), IL-17a (Th17) and TGF-β (Treg), and anti-dsDNA (B cells) in the culture media were measured by ELISA. To test the plasticity of these Treg, we treated Treg with agonistic vs antagonistic OX40L Ab in vitro, and set up the coculture experiments and determined cell proliferation and cytokine production as described above.
OX40L expression was lower in PD1loTreg from anti-PD1-treated mice when compared to PD1hiTreg from controls. OX40LhiTreg, irrespective to its Foxp3 expression, lost its ability to suppress Th and B proliferation. PD1loTreg treated with agonistic OX40L had attenuated suppressive function: there was decreased production of TGF-β, increased proliferation of Th (Th1 predominant) and increased anti-DNA production. These Treg also had increased apoptosis. Treating PD1hiTreg with antagonistic OX40L could not restore the suppressivity in Treg.
Effective induction of Treg is associated with low expression of PD-1, which permits cells to survive and perform cell suppressive function. Attenuated PD-1 expression in Treg reduces OX40L expression on Treg, which helps restore the suppressive capacity and proliferation of Treg. Increased OX40L expression overrides PD-1 signaling to deactivate and induce apoptosis in Foxp3+Treg, but reduced OX40L expression cannot recover Treg suppressivity when PD-1 signal is high. The suppressive function induced by low PD-1 expression is influenced by the intensity of OX40L expression. PD-1 and OX40L signaling most likely crosstalk to regulate the suppressive capacity and survival of Treg to achieve peripheral tolerance in SLE.
To cite this abstract in AMA style:Wong M, Hahn BH. PD-1 Signaling Interferes with OX40L to Alter the Suppressive Function and Proliferation of CD4+ Regulatory T Cells in Lupus Mice [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/pd-1-signaling-interferes-with-ox40l-to-alter-the-suppressive-function-and-proliferation-of-cd4-regulatory-t-cells-in-lupus-mice/. Accessed July 14, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pd-1-signaling-interferes-with-ox40l-to-alter-the-suppressive-function-and-proliferation-of-cd4-regulatory-t-cells-in-lupus-mice/