Session Title: T-cell Biology and Targets in Autoimmune Disease
Session Type: Abstract Submissions (ACR)
Programmed death-1 (PD-1) has been regarded as a negative regulatory signal in T cells. Our laboratory has shown that PD-1 is important in T cell regulation of autoimmunity, as treatment with neutralizing anti-PD1 Ab increased regulatory T cell function and dramatically delayed SLE onset in young BWF1 females. We hypothesized that tight regulation of PD-1 signaling is required for maintenance of functional CD4+Treg and subsequent control of autoimmunity in BWF1 mice, and that regulatory capacity of the cells is sustained at least in part by resistance to apoptosis, resulting in CD4+Treg survival, when PD-1 is expressed at a certain level – neither absent nor high.
A neutralizating Ab against PD-1 or control isotype-matched IgG were injected i.p. into BWF1 mice. Foxp3 and PD-1 expression were assessed by flow cytometry. Splenocytes from these animals were isolated for in vitro culture, and anti-PD-1 Ab at various concentrations were added in vitro to test for B cell apoptosis by Annexin V and 7-AAD, and CD4+CD25– helper T cell (Th) proliferation by CFSE. AutoAb production of anti-dsDNA and total IgG was tested by ELISA in the supernatant.
Blocking the full expression of PD-1 in vivo resulted in induction of CD4+CD25+Foxp3+Treg with reduced, but not absent, PD-1 expression. These PD-1loCD4+Treg, compared to CD4+Treg with PD-1hi expression, had increased ability to induce B cell apoptosis and to suppress Th proliferation. The PD-1loCD4+Treg suppressed syngeneic B cells production of anti-dsDNA and IgG. Apoptosis was significantly lower in the PD-1loCD4+Treg. In vitro PD-1 blockade confirmed that tight regulation of PD-1 expression is important in maintaining CD4+Treg suppressivity. By adding anti-PD-1 Ab >25 hg/ml in vitro, PD-1loCD4+Treg from mice with in vivo PD-1 blockade lost their ability to induce B cell apoptosis and suppress Th proliferation. On the other hand, PD-1hiCD4+Treg from the isotype controls became more suppressive with the presence of anti-PD-1 Ab in vitro, until its concentration was > 75hg/ml. The concentration of anti-PD-1 Ab did not affect the survival of CD4+Treg.
PD-1 expression is central in the ability of CD4+Treg to suppress autoimmunity; their PD-1 expression has to be finely tuned to permit CD4+Treg to survive and retain suppressive capacities. One mechanism by which PD-1 sustains CD4+Treg is by reducing their susceptibility to apoptosis.
A. La Cava,
B. H. Hahn,
« Back to 2012 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/pd-1-signaling-promotes-suppressive-function-of-cd4-regulatory-t-cells-in-new-zealand-black-x-new-zealand-white-f1-lupus-prone-mice-in-a-dose-dependent-manner/