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-specific 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)-7Ralpha, IL-15Rbeta, 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.
Lin
Sue-Jane
SJ
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Peacock
Craig D
CD
Bahl
Kapil
K
Welsh
Raymond M
RM
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D000954:Antigens, Surface / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D006706:Homeostasis / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D061026:Programmed Cell Death 1 Receptor; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D013997:Time Factors