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Cutting Edge: Adenosine A2a Receptor Signals Inhibit Germinal

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Cutting Edge: Adenosine A2a Receptor Signals Inhibit Germinal Cutting Edge: Adenosine A2a Receptor Signals Inhibit Germinal Center T Follicular Helper Cell Differentiation during the Primary Response to Vaccination This information is current as of September 28, 2021. Shirdi E. Schmiel, Jessica A. Yang, Marc K. Jenkins and Daniel L. Mueller J Immunol published online 16 December 2016 http://www.jimmunol.org/content/early/2016/12/15/jimmun ol.1601686 Downloaded from Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 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 © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published December 16, 2016, doi:10.4049/jimmunol.1601686 Th eJournal of Cutting Edge Immunology Cutting Edge: Adenosine A2a Receptor Signals Inhibit Germinal Center T Follicular Helper Cell Differentiation during the Primary Response to Vaccination Shirdi E. Schmiel,* Jessica A. Yang,† Marc K. Jenkins,† and Daniel L. Mueller* Adenosine A2a receptor (A2aR) signaling acts as a bar- asthma (10), autoimmunity (4, 5), and infection (11) also rier to autoimmunity by promoting anergy, inducing suggest that A2aR signaling can reduce Th1 and Th17 re- regulatory T cells, and inhibiting effector T cells. How- sponses. However, CD4 T cell differentiation during a pri- ever, in vivo effects of A2aR signaling on polyclonal mary response to foreign Ag in the context of vaccination has CD4 T cells during a primary response to foreign Ag not been assessed. Most investigations of A2aRs to date have correlated changes has yet to be determined. To address this problem, Downloaded from we immunized mice with peptide Ag 2W1S coupled in disease outcome in vivo with the in vitro modulation of to PE in CFA and treated with the selective A2aR agonist signaling in cloned T cells, TCR-transgenic T cells, or bulk CGS-21680 (CGS). 2W1S:I-Ab-specific tetramer- primary T cells. Nonetheless, Zarek et al. (4) took advantage binding CD4 T cells did not become anergic or dif- of hemagglutinin and pigeon cytochrome c peptide–specific + TCR-transgenic CD4 T cells made deficient for A2aRs ferentiate into Foxp3 regulatory T cells. Addition- 2 2 (Adora2a / ) to show in vivo that both endogenous adeno- ally, CGS treatment did not inhibit Th1 or Th17 http://www.jimmunol.org/ sine as well as an A2aR agonist can act to inhibit dangerous differentiation. However, CGS did abrogate germinal effector responses to an experimental self-antigen and pro- center T follicular helper cells, and blunted PE-specific mote the development of anergy and Tregs. More recently, germinal center B cell responses. The use of A2aR- Shehade and colleagues (11) found that activation of A2aRs deficient CD4 T cells established that this CGS effect during acute infection with Toxoplasma gondii reduced the was T cell intrinsic. Therefore, this study has identi- number of endogenous bulk IFN-g–producing CD4 T cells fied a unique role for A2aRs in regulating CD4 T cell from secondary lymphoid organs. In cancer, an investigation differentiation during vaccination. The Journal of of tumor Ag–specific CD8 polyclonal T cells in Adora2a- Immunology, 2017, 198: 000–000. deficient mice has also indicated that endogenous adenosine by guest on September 28, 2021 limits their clonal expansion in response to tumor Ags (7). denosine is a purine nucleoside that regulates a broad However, A2aR-mediated regulation of endogenous poly- spectrum of physiological responses via four different clonal Ag-specific CD4 T cells remains unknown. A G protein–coupled adenosine receptors (A1, A2a, A2b, To investigate the in vivo effects of A2aR signaling on naive and A3). Adenosine A2a receptors (A2aRs) are expressed polyclonal CD4 T cells during a primary response to foreign primarily on cells of hematopoietic origin, particularly on Ag we used a vaccination approach that allowed us to track activated cytotoxic CD8 and helper CD4 T cells (1–3). Studies Ag-specific CD4 T cells that differentiate into various T cell using mouse models of T cell–mediated autoimmune disorders lineages such as Th1, Th17, Tregs, and T follicular helper (4, 5) as well as graft-versus-host disease (6) have shown that (Tfh) cells. No reports to date have indicated a role for A2aR A2aR signaling can restore immune homeostasis by promot- signaling in Tfh differentiation despite the role of other ing the induction of T cell anergy and regulatory T cell (Treg) purinergic receptors such as P2X7 in regulating Tfh ho- differentiation. Loss of A2aR signaling in Adora2a-deficient meostasis (12). It is possible that A2aR-mediated effects on mice also leads to enhanced control of tumor growth by CD8 Tfh cells may have been overlooked due to a requirement of T cells (7). In vitro polarizing assays suggest that A2aR sig- Ag specificity between T cells and B cells during Tfh dif- naling alters CD4 T cell differentiation by inhibiting the ferentiation (13). To address this we used a vaccine that induction of Th1 (Tbet+), Th2 (GATA3+), and Th17 consists of 2W1S peptide covalently coupled to PE (14). (RORgt+) effector T cell phenotypes (8, 9). In vivo models of This allowed us to look at the interplay between endogenous *Department of Medicine, Center for Immunology, University of Minnesota Medical Address correspondence and reprint requests to Dr. Daniel L. Mueller, Department of School, Minneapolis, MN 55455; and †Department of Microbiology and Immunology, Medicine, University of Minnesota Medical School, Campus Delivery Code: 2641, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 3-186 Wallin Medical Biosciences Building, 2101 6th Street SE, Minneapolis, MN 55455 55455. E-mail address: [email protected] ORCIDs: 0000-0002-1205-5178 (J.A.Y.); 0000-0001-8009-7655 (M.K.J.). Abbreviations used in this article: A2aR, adenosine A2a receptor; B6, C57BL/6; CGS, CGS-21680; FR4, folate receptor 4; GC, germinal center; KO, knockout; LN, lymph Received for publication October 4, 2016. Accepted for publication November 27, node; Tfh, T follicular helper; Treg, regulatory T cell; WT, wild-type. 2016. This work was supported by National Institutes of Health (NIH) Grant P01AI035296 Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 (to D.L.M. and M.K.J.), an NIH Institutional Pre-Doctoral Training Grant (to S.E.S.), and a research grant from the Lupus Foundation of Minnesota (to D.L.M.). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601686 2 CUTTING EDGE: A2aR SIGNALING INHIBITS GC-Tfh DIFFERENTIATION Ag-specific 2W1S:I-Ab-specific T cells and PE-specific B cells Results (14). We initially sought to characterize polyclonal Ag-specific Activation of A2aRs during the primary response to vaccination fails to CD4 T cell anergy induction and Treg generation during induce anergy or promote the differentiation of Foxp3+ Tregs b A2aR signaling by tracking of 2W1S:I-A tetramer-binding The activation of A2aRs in many biological systems is asso- T cells in mice treated with the selective A2aR agonist CGS- ciated with the production of intracellular cAMP, a second 21680 (CGS). We discovered that CGS has no impact on the messenger known for its antiproliferative function (17). To Ag-induced clonal expansion of polyclonal 2W1S-specific investigate the effects of A2aR signaling during the primary CD4 T cells, nor does it promote the induction of anergy CD4 T cell response to Ag, we used a tetramer of the MHC II or Treg differentiation in our vaccination system. CGS did I-Ab molecule containing the 2W1S peptide to study the not appear to reduce Th1 or Th17 differentiation; instead, b in vivo proliferation and differentiation of polyclonal 2W1S: A2aR signaling directly inhibited 2W1S:I-A -driven CD4 I-Ab-specific CD4 T cells following immunization with a T cell differentiation toward the germinal center (GC)-Tfh 2W1S peptide coupled to PE in CFA. This vaccination ap- fate, and reduced cognate GC B cell responses. Therefore, this proach induces 2W1S:I-Ab-specific CD4 T cells to undergo work identifies a novel A2aR-mediated control mechanism clonal expansion and differentiation to Th1, Th17, Tregs, during vaccination that regulates CD4 T cell differentiation and Tfh lineages (14). Coupling 2W1S and PE together also and function. allows for the interplay between 2W1S-specific GC-Tfh cells and PE-reactive GC B cells. This occurs when PE-specific B cells internalize 2W1S-PE through BCR recognition of Downloaded from Materials and Methods b Mice PE resulting in the display of 2W1S:I-A complexes, and al- lows them to exchange helper signals with 2W1S:I-Ab-specific C57BL/6 (B6) wild-type (WT) mice were purchased from Charles River Breeding Laboratories under a contract from the National Cancer Institute CD4 T cells (14). The effects of A2aR activation were tested (Frederick, MD). Adora2af/f mice containing loxP sites on either side of exon by treating immunized mice twice daily with the selective 2 of the Adora2a gene (a gift from J. Linden, La Jolla Institute for Allergy and A2aR agonist CGS (2.5 mg/kg i.p.) or vehicle alone as a Immunology, La Jolla, CA) (3) were crossed with CD4-Cre mice (a gift from control (PBS) (4).
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