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Cells in Healthy Human Adults CD8 T Hi Profiles of Programmed Death-1

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Cells in Healthy Human Adults CD8 T Hi Profiles of Programmed Death-1 Phenotype, Function, and Gene Expression Profiles of Programmed Death-1 hi CD8 T Cells in Healthy Human Adults This information is current as Jaikumar Duraiswamy, Chris C. Ibegbu, David Masopust, of September 25, 2021. Joseph D. Miller, Koichi Araki, Gregory H. Doho, Pramila Tata, Satish Gupta, Michael J. Zilliox, Helder I. Nakaya, Bali Pulendran, W. Nicholas Haining, Gordon J. Freeman and Rafi Ahmed J Immunol 2011; 186:4200-4212; Prepublished online 7 Downloaded from March 2011; doi: 10.4049/jimmunol.1001783 http://www.jimmunol.org/content/186/7/4200 http://www.jimmunol.org/ References This article cites 63 articles, 33 of which you can access for free at: http://www.jimmunol.org/content/186/7/4200.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 25, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Phenotype, Function, and Gene Expression Profiles of Programmed Death-1hi CD8 T Cells in Healthy Human Adults Jaikumar Duraiswamy,*,†,1 Chris C. Ibegbu,*,† David Masopust,*,†,2 Joseph D. Miller,*,†,3 Koichi Araki,*,† Gregory H. Doho,‡ Pramila Tata,x Satish Gupta,x Michael J. Zilliox,*,† Helder I. Nakaya,*,{ Bali Pulendran,*,{ W. Nicholas Haining,‖ Gordon J. Freeman,#,** and Rafi Ahmed*,† T cell dysfunction is an important feature of many chronic viral infections. In particular, it was shown that programmed death-1 (PD-1) regulates T cell dysfunction during chronic lymphocytic choriomeningitis virus infection in mice, and PD-1hi cells exhibit an intense exhausted gene signature. These findings were extended to human chronic infections such as HIV, hepatitis C virus, and hi hepatitis B virus. However, it is not known if PD-1 cells of healthy humans have the traits of exhausted cells. In this study, we Downloaded from provide a comprehensive description of phenotype, function, and gene expression profiles of PD-1hi versus PD-1lo CD8 T cells in the peripheral blood of healthy human adults as follows: 1) the percentage of naive and memory CD8 T cells varied widely in the peripheral blood cells of healthy humans, and PD-1 was expressed by the memory CD8 T cells; 2) PD-1hi CD8 T cells in healthy humans did not significantly correlate with the PD-1hi exhausted gene signature of HIV-specific human CD8 T cells or chronic lymphocytic choriomeningitis virus-specific CD8 T cells from mice; 3) PD-1 expression did not directly affect the ability of CD8 T cells to secrete cytokines in healthy adults; 4) PD-1 was expressed by the effector memory compared with terminally differ- http://www.jimmunol.org/ entiated effector CD8 T cells; and 5) finally, an interesting inverse relationship between CD45RA and PD-1 expression was observed. In conclusion, our study shows that most PD-1hi CD8 T cells in healthy adult humans are effector memory cells rather than exhausted cells. The Journal of Immunology, 2011, 186: 4200–4212. D8 T cells are a critical component of the immune system for enhancing natural immunological control over chronic viral in- and are responsible for killing virus-infected cells and fections. C control of persistent and reactivating viruses. However, Programmed death-1 (PD-1) is a member of the CD28 family of persistent antigenic stimulation leads to CD8 T cell exhaustion, immune modulators (2–4). It is upregulated on CD8 and CD4 T cells characterized by the induction of a hypoproliferative state and loss upon activation. PD-1 binds to its ligands PD-L1 (B7-H1) or PD-L2 by guest on September 25, 2021 of the ability to produce antiviral cytokines (1). Reversing CD8 (B7-DC). Ligation of PD-1 results in dephosphorylation of signal- T cell exhaustion could provide a promising therapeutic approach ing molecules downstream of the TCR, thus dampening T cell sensitivity to antigenic stimulation. Significant evidence suggests that this pathway inhibits T cell responses upon persistent antigenic † *Emory Vaccine Center, Emory University, Atlanta, GA 30322; Department of Mi- stimulation (5–7). It has been shown that immunoreceptor tyrosine- crobiology and Immunology, Emory University, Atlanta, GA 30322; ‡Emory Biomarker Service Center, Emory University, Atlanta, GA 30322; xStrand Life Sciences, Bangalore based switch motif of PD-1 cytoplasmic tail recruits tyrosine { ‖ 560024, India; Department of Pathology, Emory University, Atlanta, GA 30322; De- phosphatases, Src homology region 2 domain-containing phos- partment of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; #Department of Medical Oncology, Dana-Farber Cancer Institute, phatase-1, and -2, which in turn interferes with proximal TCR sig- Harvard Medical School, Boston, MA 02115; and **Department of Medicine, Harvard naling pathways to affect T cell functions (8). PD-1–deficient mice, Medical School, Boston, MA 02115 when crossed to the NOD background, experience more rapid and 1Current address: Ovarian Cancer Research Center and Department of Obstetrics and severe diabetes (9–12). PD-L12/2 mice die of excessive T cell im- Gynecology, University of Pennsylvania School of Medicine, Philadelphia, PA. munopathology following chronic lymphocytic choriomeningitis 2 Current address: Department of Microbiology and Center for Immunology, Univer- virus (LCMV) infection (13). We have shown that PD-1 regulates sity of Minnesota, Minneapolis, MN. T cell dysfunction during chronic LCMV infection in mice and 3Current address: Centers for Disease Control and Prevention, Atlanta, GA. demonstrated that in vivo blockade of PD-1–PD-L1 interactions: 1) Received for publication June 17, 2010. Accepted for publication January 29, 2011. restores effector functions of exhausted CD8 T cells; and 2) leads to This work was supported by National Institutes of Health Grant P01 AI080192-01 (to substantial reduction in virus replication (13). These findings were R.A.) and Grand Challenges in Global Health Initiative Grant 05GCGH0 (to R.A.). extended to HIV, hepatitis B virus (HBV), and hepatitis C virus The sequences presented in this article have been submitted to the Gene Expression Omnibus under accession number GSE26495. (HCV) infections in humans and SIV infection in macaques, in- Address correspondence and reprint requests to Dr. Rafi Ahmed, Emory Vaccine dicating that PD-1 overexpression on T cells plays an important role Center and Department of Microbiology and Immunology, Emory University School in these infections (14–20). These data suggest that abrogation of of Medicine, 1510 Clifton Road, G211, Rollins Research Center, Atlanta, GA 30322. the PD-1 inhibitory pathway may contribute to successful treatment E-mail address: [email protected] of life-threatening chronic infections in humans. Abbreviations used in this article: CMV, cytomegalovirus; DEG, differentially ex- pressed gene; GSEA, gene set enrichment analysis; HBV, hepatitis B virus; HCV, hepa- In addition to chronic viral infections, PD-1 inhibitory pathway titis C virus; KIR, killer cell Ig-like receptor; KLR, killer cell lectin-like receptor; plays an important role in tumors. Expression of PD-L1 is reported LCMV, lymphocytic choriomeningitis virus; PD-1, programmed death-1; TCM,central on a variety of human tumors. Expression of PD-L1 by tumor cells memory T cell; T , effector memory T cell; T , effector memory RA T cell. EM EMRA correlates with a very poor prognosis, suggesting that cancer cells Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 purloin this inhibitory pathway to evade the host immune response www.jimmunol.org/cgi/doi/10.4049/jimmunol.1001783 The Journal of Immunology 4201 (21, 22). Recent studies also show that the tumor microenviron- For this reason, we examined the levels of PD-1 expression on ment may play a role in the induction and maintenance of PD-1 the resting CD8 T cells from healthy individuals. We found that expression on tumor-reactive T cells and that expression of PD-1 PD-1 is expressed by ∼60% of memory CD8 T cells in the pe- on tumor-infiltrating lymphocytes impairs the antitumor immune ripheral blood cells of healthy humans. First, we analyzed the responses in humans (23). gene expression profile of PD-1hi CD8 T cells in the peripheral Although PD-1 expression on virus-specific CD8 T cells of blood cells of healthy human adults in comparison with PD-1lo chronically infected patients is well described, little is known about and naive CD8 T cells. We found that the gene expression profiles its pattern expression on CD8 T cells of healthy human adults. of PD-1hi and PD-1lo CD8 T cells were closely related. Then Although PD-1 contributes to functional defects of memory CD8 we compared gene expression profiles of the PD-1hi CD8 T cell T cells, deficiencies in the PD-1 are associated with autoimmune subset of healthy humans with PD-1hi exhausted signatures of diseases (5, 10, 24). PD-1 is transiently expressed on activated HIV-specific human CD8 T cells or LCMV-specific CD8 T cells T cells, and frequent TCR stimulation is required to maintain PD- from chronically (LCMV clone-13 strain) infected mice. We 1 expression (13, 25, 26). However, the proportion of activated found that signatures of genes characteristic of exhausted CD8 versus exhausted cells expressing PD-1 is not known.
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