Title

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

GSBS Program

Biochemistry & Molecular Pharmacology

UMMS Affiliation

Graduate School of Biomedical Sciences; Department of Pathology; Department of Molecular Genetics and Microbiology

Date

9-6-2007

Document Type

Article

Medical Subject Headings

Animals; Annexin A5; Antigens, Ly; Antigens, Surface; Apoptosis Regulatory Proteins; Cell Proliferation; Cytokines; Homeostasis; Immunologic Memory; Lymphocyte Activation; Male; Mice; T-Lymphocytes; Time Factors

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

Citation: J Exp Med. 2007 Oct 1;204(10):2321-33. Epub 2007 Sep 4. Link to article on publisher's site

Related Resources

Link to Article in PubMed