Blockade of Programmed death-1 induces functional CD4+ regulatory T cells to resist apoptosis in (New Zealand Black x New Zealand White)F1 lupus-prone mice (115.25)

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Abstract PD-1 is a negative regulatory signal in T cells. We hypothesize that regulation of PD-1 signaling is required for maintenance of functional regulatory T cells (Treg) and subsequent control of autoimmunity in BWF1 mice, and that regulatory capacity of the cells is sustained in part by resistance to apoptosis, resulting in Treg survival. By toleration with an artificial peptide pCons, we have shown induction of CD4+ and CD8+ Foxp3+Treg with reduced of PD-1 expression decrease anti-dsDNA and nephritis and prolong survival. The same outcomes are observed when PD-1 expression is blocked by a neutralizing antibody. Here, anti-PD1 or pCons treatments maintained total numbers of functional suppressive Foxp3+CD4+CD25+ T cells between 10 and 40 weeks of age. The decline in IL-2 was significantly delayed by anti-PD1, and TGF-β production was increased. These CD4+Treg were resistant to spontaneous apoptosis, suppressed CD4+CD25- T cell proliferation, and induced apoptosis in B cells. In particular, Fas and FasL are two candidate molecules in the apoptotic pathways that were upregulated in splenic CD4+Treg upon pCons-tolerization or PD-1 blockade. To conclude, PD-1 is central in control of some regulatory T cells that suppress autoimmunity; their PD-1 expression may need fine tuning to permit the cells to survive and retain suppressive capacities. A mechanism by which PD-1 sustains these Treg is by reducing their susceptibility to apoptosis, which may relate to altering Fas/FasL pathway.