Targeting PD‐1 or ICOS pathways does not rescue decreased CD3‐induced proliferation of aged T cells

The co‐stimulatory molecules ICOS and PD‐1, and their ligands (ICOSL and PD‐L1/PD‐L2 respectively), regulate T cell activation and tolerance in young animals. However, their role in the immune deficiency associated with aging is still unknown. We therefore compared the expression of these molecules in the spleen, lymph nodes and lungs from young and aged mice. In aged mice the expression of PD‐L1 was higher on plasmacytoid dendritic cells (DC), whereas the expression of PD‐L2 was higher on all DC subsets examined. While constitutive levels of ICOS and PD‐1 were more elevated on CD4 + T cells from aged mice, in vitro anti‐CD3‐mediated activation increased both PD‐1 and ICOS expression on young, but not old, CD4 + T cells. Interestingly, the lower proliferation of old T cells was not rescued by ICOS stimulation or blockade of the PD‐1 pathway. PD‐1 or PD‐L1 blockade enhanced IFNγ production by old T cells, but had limited impact on IL‐13 and IL‐17 contrary to what we observed in young T cells. Our data suggest that, despite higher basal ICOS and PD‐1 expression, these pathways may be less efficient at regulating T cell activation in aged animals. This finding could be due to intrinsic defects in the signaling pathways and/or to extrinsic mechanisms of dysregulation, such as the increased number of functional regulatory T cells in aged mice. Supported by AG025149, HL67736, ALA grant to IPL.