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Dependent Supereffector CD8 T Cells That Become IL-7 Pathway To CD134 Costimulation Couples the CD137 Pathway to Induce Production of Supereffector CD8 T Cells That Become IL-7 Dependent This information is current as of September 26, 2021. Seung-Joo Lee, Robert J. Rossi, Sun-Kyeong Lee, Michael Croft, Byoung S. Kwon, Robert S. Mittler and Anthony T. Vella J Immunol 2007; 179:2203-2214; ; doi: 10.4049/jimmunol.179.4.2203 Downloaded from http://www.jimmunol.org/content/179/4/2203 References This article cites 71 articles, 35 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/179/4/2203.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 26, 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 © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology CD134 Costimulation Couples the CD137 Pathway to Induce Production of Supereffector CD8 T Cells That Become IL-7 Dependent1 Seung-Joo Lee,* Robert J. Rossi,* Sun-Kyeong Lee,† Michael Croft,‡ Byoung S. Kwon,§ Robert S. Mittler,¶ and Anthony T. Vella2* The TNFR superfamily members 4-1BB (CD137) and OX40 (CD134) are costimulatory molecules that potently boost CD8 and CD4 T cell responses. Concomitant therapeutic administration of agonist anti-CD137 and -CD134 mAbs mediates rejection of established tumors and fosters powerful CD8 T cell responses. To reveal the mechanism, the role of CD137 expression by specific CD8 T cells was determined to be essential for optimal clonal expansion and accumulation of effector cells. Nonetheless, dual costimulation induced production of supereffector CD8 T cells when either the specific T cells or the host alone bore CD137. Downloaded from Perhaps surprisingly, the total absence of CD137 prevented anti-CD134 augmentation of supereffector differentiation demon- strating an unappreciated link between these related pathways. Ultimately, it was reasoned that these powerful dual costimulatory responses involved common ␥ family members, and we show substantial increases of CD25 and IL-7R␣-chain expression by the specific CD8 T cells. To investigate this further, it was shown that IL-7 mediated T cell accumulation, but importantly, a gradual and preferential effect of survival was directed toward supereffector CD8 T cells. In fact, a clear enhancement of effector differ- entiation was demonstrated to be proportional to the increasing amount of IL-7R␣ expression by the specific CD8 T cells. http://www.jimmunol.org/ Therefore, dual costimulation through CD137 and CD134 drives production and survival of supereffector CD8 T cells through a distinct IL-7-dependent pathway. The Journal of Immunology, 2007, 179: 2203–2214. he role of TNFR superfamily members for T cell costimu- Previously, we demonstrated that certain combinations of dual lation has received a great deal of attention, especially in costimulation such as combined activation through CD137 and T their ability to potently stimulate effector T cells, impact CD134 induced a profound effect on the generation and quality of tolerance, and deliver long-term survival signals to specific T cells peptide-specific CD8 T cells (23). Stimulation of both costimula- (1). In their own right, signaling through CD137 (4-1BB) and tors, in a protocol that mimicked immunotherapy (24), induced CD134 (OX40) have been shown to support very similar responses CD8 T cell clonal expansion and effector T cell generation, which by guest on September 26, 2021 although not identical. CD134 is expressed early after CD4 T cell was accentuated in a mouse tumor cell model. Similar data using activation and mediates induction of effector T cell differentiation a wider variety of experimental murine tumor models was also (2–4). Recent reports have also shown that CD134 can costimulate reported (25). Additionally, recent data expanded upon these re- T regulatory cells (5), influence bystanding cells, and also facilitate sults by demonstrating that concomitant immunotherapy with anti- accumulation of effector T cells in pulmonary tissue (6, 7). In DR5, -CD137, and -CD40 mAbs were able to eradicate pre-estab- much the same way, stimulation of CD137 induces very similar lished tumors (26). Finally, dual costimulation induced by CD80 effects in populations of peptide-specific CD8 T cells (1, 8, 9). In and CD137L was shown to enhance CD8 T cell responses in lym- particular, CD137-stimulated T cells display enhanced cytotoxicity phocyte populations from long-term infected HIVϩ donors (27). and cytokine production (1, 8, 10), while at the same time endow- Therefore, these data collectively suggest that combined stimula- ing CD8 T cells to persist for long periods of time (9, 11–13), as tion of costimulatory pathways can lead to efficacious immuno- well as developing suppressor function (14–19). Nevertheless, therapy of tumors in humans as well as having the potential for both costimulatory pathways can overlap in their effects on CD4 vaccine development. and CD8 T cell subpopulations (10, 12, 20–22). Although the potency of dual costimulation is notable, the mechanism explaining why two costimulators can be synergistic is unclear. This is particularly interesting for CD137 and CD134, *Department of Immunology and †Division of Endocrinology, Department of Med- where surface expression on T cells is relatively similar (28, 29), icine, University of Connecticut Health Center, Farmington, CT 06030; ‡Division of and both molecules use comparable, but perhaps not identical, sig- Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA naling pathways (1, 30, 31). A significant difference, however, is 92121; §Immunomodulation Research Center, University of Ulsan, Ulsan, South Ko- rea; and ¶Department of Surgery and Emory Vaccine Center, Emory University that in general CD134 predominantly stimulates CD4 over CD8 T School of Medicine, Atlanta, GA 30329 cells (2, 32–35), and the opposite is the case for CD137 (8, 35–38). Received for publication February 28, 2007. Accepted for publication June 11, 2007. Furthermore, CD137 is widely expressed on many different cell 3 The costs of publication of this article were defrayed in part by the payment of page types including dendritic cells (DCs) (36, 39–44), but based on charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by National Institutes of Health Grants R01 AI42858 and AI52108 (to A.T.V.). 3 ␥ ␥ Abbreviations used in this paper: DC, dendritic cell; c, common ; PLN, peripheral 2 Address correspondence and reprint requests to Dr. Anthony T. Vella, Department lymph node; MLN, mesenteric lymph node; WT, wild type. of Immunology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030. Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 www.jimmunol.org 2204 DUAL COSTIMULATION GENERATES SUPEREFFECTOR CD8 T CELLS current data, CD134 does not appear to be as pervasively ex- and then in collagenase solution (Invitrogen Life Technologies) for 1 h. pressed (3, 4, 45). In this report, some of these concepts were After being crushed through a cell strainer, cells were resuspended in 44% reinforced and extended using the OT-I CD8 T cell transfer model Percoll (Amersham Biosciences) and layered above a 67% Percoll cushion. After centrifugation, cells were isolated from the interface and washed. interfaced with immunotherapeutic use of agonist anti-CD137 and -CD134 mAbs. It is shown that an optimal dual costimulatory ef- In vitro culturing fect through CD137 and CD134 required CD137 expression on the In Fig. 5, day 2.5 spleens were treated with collagenase (Roche) at 37°C for specific CD8 T cells. Specifically, effector differentiation was still 30 min. One hundred microliters of 0.1 mM EDTA was added to inactivate retained when T cells were CD137 deficient, but accumulation was the activity of collagenase. Day 4 spleens were directly applied to a cell substantially reduced in lymphoid and peripheral sites. Second, strainer. Splenocytes were crushed through a cell strainer and run through CD134 costimulation was largely ineffectual at inducing superpro- a nylon wool column (PerkinElmer Life and Analytical Sciences) to re- move APCs. Cells were incubated with biotin-, PE-, or FITC-conjugated duction of effector cytokines in the absence of the CD137 pathway. anti-CD45.1 mAb (eBioscience), and then labeled with anti-biotin, or anti- These results suggested that dual costimulation induced effects PE, or anti-FITC microbead (Miltenyi Biotec) according to the manufac- on both the specific T cells and host APCs, and revealed an turer’s recommendation. CD45.1ϩ cells were selected by MACS columns (Miltenyi Biotec). After washing, purity of CD45.1ϩ OT-I was measured unappreciated interdependent link of CD137 function for ϩ CD134 costimulation. Delving deeper, we detected a preferen- by flow cytometry and was typically 80–95% CD45.1 cells. The purified ␥ ␥ OT-I T cells were resuspended in CTM (MEM containing amino acids, tial increase of the common ( c) cytokine receptors CD25 and salts, antibiotics, and FBS), and 100,000 cells were placed into a well of a IL-7R␣ (CD127) on the dual costimulated CD8 T cells vs the 96-well plate and cultured at 37°C. For in vitro experiment, recombinant individually costimulated cells. Purified CD8 T cells responded mouse IL-7 (PeproTech) was added at 10 ng/ml at the beginning of the to IL-7 by surviving better in an overnight culture, but more culture.
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