The molecular signature of murine T cell homeostatic proliferation reveals both inflammatory and immune inhibition patterns

• Type of Material: Article
• Authors: Karen A. Fortner, University of Vermont; Jeffrey P. Bond, University of Vermont; James W. Austin, Emory University; Jeremy Boss, Emory University; Ralph C. Budd, University of Vermont
• Language: English
• Date: 2017-08-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier Ltd
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jaut.2017.05.003
• Title of Journal or Parent Work: Journal of Autoimmunity
• ISSN: 0896-8411
• Volume: 82
• Start Page: 47
• End Page: 61
• Grant/Funding Information: The target preparation and microarray analysis were performed in the Vermont Genetics Network Microarray Facility, which is supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103449.; This work was supported by the National Institute of Health (AI036333 and GM103496 to R. C. B. and AI113021 to J. M. B.).; We acknowledge the NIH Tetramer Core Facility (contract HHSN272201300006C) for provision of CD1d tetramers.
• Keywords: RHEUMATOID-ARTHRITIS; CD8(+) T cells; Science & Technology; LYMPHOCYTE-ACTIVATION; Homeostatic proliferation; TYROSINE PHOSPHORYLATION; Life Sciences & Biomedicine; VIRAL-INFECTION; EFFECTOR FUNCTION; APOPTOSIS REGULATORS FAS; AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; Immunology; Inhibitory proteins; Fas (CD95); INFLUENZA VACCINATION; IN-VIVO; Cytolytic proteins; LPR MICE; T lymphocytes
• Research Categories: Health Sciences, Immunology; Health Sciences, Medicine and Surgery; Biology, Microbiology

Abstract

T lymphocyte homeostatic proliferation, driven by the engagement of T cell antigen receptor with self-peptide/major histocompatibility complexes, and signaling through the common γ-chain-containing cytokine receptors, is critical for the maintenance of the T cell compartment and is regulated by the Fas death receptor (Fas, CD95). In the absence of Fas, Fas-deficient lymphoproliferation spontaneous mutation (lpr) mice accumulate homeostatically expanded T cells. The functional consequences of sequential rounds of homeostatic expansion are not well defined. We thus examined the gene expression profiles of murine wild-type and Fas-deficient lpr CD8+T cell subsets that have undergone different amounts of homeostatic proliferation as defined by their level of CD44 expression, and the CD4−CD8−TCRαβ+T cell subset that results from extensive homeostatic expansion of CD8+T cells. Our studies show that recurrent T cell homeostatic proliferation results in global gene expression changes, including the progressive upregulation of both cytolytic proteins such as Fas-Ligand and granzyme B as well as inhibitory proteins such as programmed cell death protein 1 (PD-1) and lymphocyte activating 3 (Lag3). These findings provide an explanation for how augmented T cell homeostatic expansion could lead to the frequently observed clinical paradox of simultaneous autoinflammatory and immunodeficiency syndromes and provide further insight into the regulatory programs that control chronically stimulated T cells.