Programmed death-1 (PD-1) defines a transient and dysfunctional oligoclonal T cell population in acute homeostatic proliferation

The host responds to lymphopenic environments by acute homeostatic proliferation, which is a cytokine- and endogenous peptide- driven expansion of lymphocytes that restores the numbers and diversity of T cells. It is unknown how these homeostatically proliferating ( HP) cells are ultimately controlled. Using a system where lymphocytic choriomeningitis virus immune C57BL/ 6 splenocytes were transferred into lymphopenic T cell - deficient hosts and allowed to reconstitute the environment, we defined the following three populations of T cells: slowly dividing Ly6C+ cells, which contained bona fide virus- specifi c memory cells, and more rapidly dividing Ly6C - cells segregating into programmed death ( PD)- 1+ and PD- 1 - fractions. The PD- 1 + HP cell population, which peaked in frequency at day 21, was dysfunctional in that it failed to produce interferon gamma or tumor necrosis factor alpha on T cell receptor ( TCR) stimulation, had down- regulated expression of interleukin ( IL)- 7R alpha, IL-15R beta 15R beta, and Bcl- 2, and reacted with Annexin V, which is indicative of a preapoptotic state. The PD- 1 + HP cells, in contrast to other HP cell fractions, displayed highly skewed TCR repertoires, which is indicative of oligoclonal expansion; these skewed repertoires and the PD- 1 + population disappeared by day 70 from the host, presumably because of apoptosis. These results suggest that PD- 1 may play a negative regulatory role to control rapidly proliferating and potentially pathogenic autoreactive CD8 + T cells during homeostatic reconstitution of lymphopenic environments.