Infection and Regulates Their Function Expressed on CMV

B and T Lymphocyte Attenuator Is Highly Expressed on CMV-Specific T Cells during Infection and Regulates Their Function This information is current as Nacer-Eddine Serriari, Françoise Gondois-Rey, Yves of September 28, 2021. Guillaume, Ester B. M. Remmerswaal, Sonia Pastor, Nassima Messal, Alemseged Truneh, Ivan Hirsch, René A. W. van Lier and Daniel Olive J Immunol 2010; 185:3140-3148; Prepublished online 6 August 2010; Downloaded from doi: 10.4049/jimmunol.0902487 http://www.jimmunol.org/content/185/6/3140 References This article cites 43 articles, 21 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/185/6/3140.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • 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 © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology B and T Lymphocyte Attenuator Is Highly Expressed on CMV-Specific T Cells during Infection and Regulates Their Function Nacer-Eddine Serriari,* Françoise Gondois-Rey,* Yves Guillaume,* Ester B. M. Remmerswaal,† Sonia Pastor,* Nassima Messal,* Alemseged Truneh,‡ Ivan Hirsch,* Rene´ A. W. van Lier,† and Daniel Olive* B and T lymphocyte attenuator (BTLA), like its relative programmed cell death-1 (PD-1), is a receptor that negatively regulates murine T cell activation. However, its expression and function on human T cells is currently unknown. We report in this study on the expression of BTLA in human T cell subsets as well as its regulation on virus-specific T cells during primary human CMV infection. BTLA is expressed on human CD4+ T cells during different stages of differentiation, whereas on CD8+ T cells, it is found on naive Downloaded from T cells and is progressively downregulated in memory and differentiated effector-type cells. During primary CMV infection, BTLA was highly induced on CMV-specific CD8+ T cells immediately following their differentiation from naive cells. After control of CMV infection, BTLA expression went down on memory CD8+ cells. Engagement of BTLA by mAbs blocked CD3/CD28- mediated T cell proliferation and Th1 and Th2 cytokine secretion. Finally, in vitro blockade of the BTLA pathway augmented, as efficient as anti–PD-1 mAbs, allogeneic as well as CMV-specific CD8+ T cell proliferation. Thus, our results suggest that, like PD-1, BTLA provides a potential target for enhancing the functional capacity of CTLs in viral infections. The Journal of http://www.jimmunol.org/ Immunology, 2010, 185: 3140–3148. mmune responses are controlled by cosignaling molecules and produce effector cytokines (4–10), raising the possibility that that regulate T lymphocyte activation either positively or neg- this pathway has been exploited by a variety of viruses to establish I atively. The B7/CD28 family of negative receptors include chronic infection. CTLA4, programmed cell death 1 (PD-1) (also called CD279), BTLA (CD272) is the most recently described member of the and a recently identified molecule known as B and T lymphocyte CD28 family. BTLA was first identified as a transcript highly attenuator (BTLA) (1, 2). In mice, PD-1 is found on activated, but specific to Th1 cells (11), but it was later shown to also be ex- by guest on September 28, 2021 not resting, T and B cells (3). PD-1 has two ligands called PD-L1 pressed by thymocytes (12). BTLA interacts with herpes virus- (also called B7-H1 and CD274) and PD-L2 (also called B7-DC entry mediator (HVEM), a member of the TNFR family (13). The and CD273), which have distinct patterns of expression. Recently, interaction of BTLA, an Ig superfamily member, and HVEM, it has been reported that PD-1 is highly expressed on exhausted a costimulatory receptor homologous to TNFR, is quite unique murine T cells during chronic lymphocytic choriomeningitis virus in that it defines a cross talk between these two families of struc- (LCMV) infection and that it is upregulated on human HIV and turally distinct receptors (14). BTLA is expressed on a broad array HCV-specific CD8+ T cells. Blocking of PD-1/PD-1 ligand inter- of murine immune cells, including B cells, CD4+ T cells, CD8+ actions reinvigorates exhausted T cells, allowing them to expand T cells, NK cells, macrophages, and dendritic cells (DCs). Like PD-1, BTLA contains a membrane proximal ITIM and membrane distal immunoreceptor tyrosine-based switch motif (ITSM). *Institut National de la Sante´ et de la Recherche Me´dicale Unite´ Mixte de Recherche 891, Institut Paoli Calmettes, Universite´ de la Me´diterraneé, Infrastructures en Biologie Disruption of either the ITIM or ITSM abrogated the ability of BTLA Sante et Agronomie Cancer Immunomonitoring Platform, Institut Fe´de´ratif de Re- to recruit either Src homology region 2 domain-containing phospha- † cherche 137, Marseille, France; Department of Experimental Immunology, Academic tase (SHP) 1 or SHP2 (15), suggesting that BTLA recruits SHP1 and Medical Center, Amsterdam, The Netherlands; and ‡Synaptex, Sudbury, MA 01776 SHP2 in a manner distinct from PD-1 and that both tyrosine motifs Received for publication July 30, 2009. Accepted for publication July 1, 2010. are required to block T cell activation. The human BTLA cytoplasmic This work was supported by Institut National de la Sante´ et de la Recherche Me´d- icale, Institut Paoli Calmettes, Groupement des Entreprises Francaises dans la Lutte region also contains two Grb-2 binding sites, YDN and YSN (16). Contre le Cancer, Infrastructures en Biologie Sante et Agronomie, and Association PD-1 and BTLA are both implicated in the negative regulation of pour la Recherche sur le Cancer. immune responses. PD-1, moreover, may not only to be involved in Address correspondence and reprint requests to Dr. Daniel Olive, Institut National de peripheral tolerance control, but also in immune exhaustion in la Sante´ et de la Recherche Me´dicale Unite´ Mixte de Recherche 891, Centre de Recherche en Cance´rologie de Marseille, 232 Boulevard de Sainte-Marguerite, Mar- chronic infections and cancer. The role of BTLA appears to be lim- seille, 13009, France. E-mail address: [email protected] ited to lymphocyte activation as shown in BTLA-deficient mice, Abbreviations used in this paper: aAPC, artificial APC; BTLA, B and T lymphocyte which have normal lymphoid organ development. However, these attenuator; CM, central memory; CsA, cyclosporin A; DC, dendritic cell; EM, effector mice display hyperproliferative T cell responses to TCR-mediated memory; HVEM, herpes virus-entry mediator; iDC, immature dendritic cell; IE, im- mediate-early; ITSM, immunoreceptor tyrosine-based switch motif; LCMV, lympho- activation (11, 17). Furthermore, loss of BTLA function leads to cytic choriomeningitis virus; mDC, mature dendritic cell; mfi, median of fluorescence; increased susceptibility to experimental autoimmune encephalo- MHC I, MHC class I; PD-1, programmed cell death-1; SHP, Src homology region 2 myelitis and MHC-mismatched allograft rejection, supporting domain-containing phosphatase; TEMRA, effector memory CD45RA+ T cell. a role for BTLA in modulating T cell activation and effector Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 responses (11, 18). In contrast to PD-1, BTLA is not upregulated www.jimmunol.org/cgi/doi/10.4049/jimmunol.0902487 The Journal of Immunology 3141 in the LCMV murine model of chronic infection, and conse- Alexa Fluor 488-conjugated anti-BTLA mAbs and a corresponding line- quently, it is not supposed to play a prominent role in the function age-specific mAb: anti-CD3–ECD (Beckman Coulter, Paris, France), anti- of antiviral-specific CD8 T cells, at least during chronic infection CD27–allophycocyanin-Alexa 750 (Invitrogen), anti-CD4–Pacific Blue, anti- CD8–Alexa 700, or anti-CD45RA–PE-Cy7 (all from Becton Dickinson). (19). Yet, its role in the specific human antiviral T cell responses Dead cells were eliminated using aqua LIVE/DEAD Fixable Dead Cell Stain has not been demonstrated. Kit (Invitrogen), and nonstudied cell populations were excluded from the Hence, we have performed a comprehensive study of human analysis by the use of anti-CD14 and anti-CD19–PC5 mAbs (Beckman BTLA expression on the subsets of CD4+ and CD8+ T cells and Coulter). Cells were washed twice in cold PBS with 2% FCS and 0.02% sodium azide, fixed in 4% paraformaldehyde, and data were acquired on an compared its expression to that of its relative PD-1. In addition, FACS LSR II SORP 4 lasers flow cytometer (BD Immunocytometry Systems, we have analyzed BTLA expression in the course of CMV-specific Le Pont De Claix, France) and analyzed with FlowJo (Tree Star, Ashland, CD8+ T cell differentiation. Finally, we have compared the effect OR). PBMCs from transplant recipients were washed in PBS containing of PD-1 and BTLA on T cell activation of T cell-specific alloge- 0.01% (w/v) NaN3 and 0.5% (w/v) BSA. One million PBMCs were incu- neic and CMV responses in vitro. bated with an appropriate concentration of tetrameric complexes in a small volume for 30 min at 4˚C, protected from light. Fluorescence-labeled mAbs were then added and incubated for 30 min at 4˚C, protected from light, Materials and Methods at concentrations according to the manufacturer’s instructions.

Load more