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Cells T+ HLA-DR + Processing in Human CD4 Cathepsin S

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Cells T+ HLA-DR + Processing in Human CD4 Cathepsin S Cathepsin S Regulates Class II MHC Processing in Human CD4 + HLA-DR+ T Cells This information is current as Cristina Maria Costantino, Hidde L. Ploegh and David A. of September 26, 2021. Hafler J Immunol 2009; 183:945-952; Prepublished online 24 June 2009; doi: 10.4049/jimmunol.0900921 http://www.jimmunol.org/content/183/2/945 Downloaded from References This article cites 47 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/183/2/945.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • 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 by guest on September 26, 2021 *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 © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Cathepsin S Regulates Class II MHC Processing in Human CD4؉ HLA-DR؉ T Cells1 Cristina Maria Costantino,* Hidde L. Ploegh,† and David A. Hafler2* Although it has long been known that human CD4؉ T cells can express functional class II MHC molecules, the role of lysosomal proteases in the T cell class II MHC processing and presentation pathway is unknown. Using CD4؉ T cell clones that constitutively express class II MHC, we determined that cathepsin S is necessary for invariant chain proteolysis in T cells. CD4؉HLA-DR؉ T cells down-regulated cathepsin S expression and activity 18 h after activation, thereby ceasing nascent class II MHC product formation. This blockade resulted in the loss of the invariant chain fragment CLIP from the cell surface, suggesting that—like professional APC—CD4؉ HLA-DR؉ cells modulate self-Ag presentation as a consequence of activation. Furthermore, cathepsin S expression and activity, and concordantly cell surface CLIP expression, was reduced in HLA-DR؉ CD4؉ T cells as compared with B cells both in vitro and ex vivo. The Journal of Immunology, 2009, 183: 945–952. Downloaded from D4ϩ T cells are activated by TCR engagement of pep- surrogate substrate and trafficking chaperone (11). As the MHC:Ii tide/class II MHC complexes on APCs to initiate an complex migrates through the endo/lysosomal compartment, res- C adaptive immune response, but can themselves also ex- ident proteases systematically degrade the this chaperone, leaving press class II MHC (1, 2). The expression of class II MHC on only the Ii fragment CLIP to occlude the class II MHC binding CD4ϩ T cells occurs in most mammalian species (3), the exception pocket. These same proteases hydrolyze self and foreign proteins http://www.jimmunol.org/ being mice, which do not transcribe the CIITA promoter III in to generate peptide epitopes, which ultimately displace CLIP and CD4ϩ T cells (4, 5). are loaded into the class II MHC binding pocket with the aid of the In the human system, expression of HLA-DR, the most preva- loading molecule HLA-DM (12). lent class II MHC molecule, was first described as a marker of Key proteolytic regulators of class II MHC processing have activated T cells (2). Patients with chronic autoimmune disease, been identified in professional APC with the use of knock-out mice inflammation, and the recent recipients of immunizations exhibited and specific protease inhibitors (13, 14). Blockade of Ii degrada- a higher frequency of HLA-DRϩ T cells in the peripheral blood as tion results in the accumulation of Ii intermediates and can lead to compared with healthy donors (6). Yet, for human CD4ϩ T cells, a corresponding decrease in surface expression of class II MHC HLA-DR is more than a biomarker of activation. Class II MHC on products (15, 16). In human B cell lines, treatment with the pan- by guest on September 26, 2021 these cells is functional and can be used to present peptide Ag to cysteine protease inhibitor leupeptin or the cathepsin S inhibitor activate responder CD4ϩ T cells in vitro (7–9). Furthermore, re- leucine-homophenylalanine-vinyl sulfone (LHVS) blocks success- cent studies have identified HLA-DR expression on CD4ϩ T cells ful degradation of Ii (17). Characterization of cathepsin S (CatS) in the blood of healthy donors, specifically a subset of CD4ϩ knock-out mice has further implicated CatS in the terminal cleav- CD25high FoxP3ϩ natural regulatory T cells, and suggest that age of Ii to yield CLIP in professional APC (13). Further studies, HLA-DR may have a functional role in these cells (10). however, have demonstrated a cell type-specific role for cysteine Although the class II MHC processing and presentation pathway proteases in these later stages of Ii processing. CatL in thymic has been studied extensively in professional APC, this pathway in epithelial cells and CatF in macrophages can also perform this human CD4ϩ T cells has not been characterized. This is not a cleavage (18) (19). trivial issue, as many of the enzymes involved in the generation of Although B and T cells are derived from a common precursor, antigenic peptides are not ubiquitously expressed. HLA-DR mat- these cells ultimately differentiate into functionally unique lineages uration is regulated by the invariant chain (Ii),3 which acts as a with distinct trafficking pathways, organization, and composition within their intracellular processing compartments. This prompted us to explore in detail the biosynthesis of human class II MHC products *Division of Molecular Immunology, Center for Neurologic Diseases, Brigham and in MHC-identical B and T cells. In this study, we demonstrate, using Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115; ϩ † CD4 T cell clones, that CatS is a key enzyme required for proteol- Whitehead Institute, Department of Biology, Massachusetts Institute of Technology, ϩ ϩ Cambridge, Massachusetts 02142 ysis of Ii in CD4 HLA-DR T cells. We find that activation-induced Received for publication March 23, 2009. Accepted for publication May 19, 2009. regulation of CatS expression and activity leads to the down-regula- ϩ ϩ The costs of publication of this article were defrayed in part by the payment of page tion of CLIP expression in CD4 HLA-DR T cells both in vitro and ϩ ϩ charges. This article must therefore be hereby marked advertisement in accordance ex vivo. Our data indicates that CD4 HLA-DR T cells modulate with 18 U.S.C. Section 1734 solely to indicate this fact. peptide epitope presentation postactivation, and furthermore suggests 1 This work was supported by National Institutes of Health grants. that presentation of non-CLIP self-peptide may be integral to the func- 2 Address correspondence and reprint requests to Dr. David Hafler, Harvard Medical tion of class II MHC on these cells. School, 77 Avenue Louis Pasteur, Room 641, Boston, MA 02115. E-mail address: dhafl[email protected] 3 Abbreviations used in this paper: Ii, invariant chain; LHVS, leucine-homopheny- Materials and Methods lalanine-vinyl sulfone; Cat, cathepsin; AEP, asparagine endopeptidase; EBV, Epstein- Cell culture reagents and Abs Barr Virus. Cells were cultured in RPMI 1640 medium supplemented with 2 mM Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 L-glutamine, 5 mM HEPES, 100 U/ml penicillin/streptomycin (all from www.jimmunol.org/cgi/doi/10.4049/jimmunol.0900921 946 INVARIANT CHAIN PROTEOLYSIS IN HUMAN CD4ϩ T CELLS BioWhittaker), 0.5 mM sodium pyruvate, 0.5 mM nonessential amino ac- Results 2 ids (from Life Technologies) in 96-well U-bottom plates or 25 cm vented Establishment of CD4ϩ HLA-DRϩ T cell clones flasks (CoStar). T cell clone medium additionally received 5% human AB serum (Meditech) and 25 U/ml recombinant human IL-2 (Tecin, National Class II MHC is a traditional biomarker of activated human CD4ϩ Cancer Institute). The medium for the Epstein-Barr Virus (EBV)-trans- T cells (2), but relatively little is known about endogenous class II formed B cell lines was supplemented with 8% FBS. The ␣CD3 (UCHT1 ␣ ␣ ␣ expression, processing, and Ag presentation in these adaptive, non- and Hit3a), CD4 (RPA-T4), CD28 (CD28.2 and 3D10), CLIP/ ϩ HLA-DR (CerCLIP), ␣HLA-DR (L243 and Tu¨36), ␣ class II MHC (Tu¨39), professional APC. To assess class II MHC expression in CD4 T ϩ ␣HLA-DM (MaP.DM1), and ␣CD19 (1D3) Abs were purchased from BD cells at the single cell level, we generated CD4 T cell clones from Pharmingen. the peripheral blood of healthy donors. We propagated these Cell isolation clones in APC-free cultures to ensure that our analysis was re- stricted to endogenous class II MHC expression and would ex- Whole mononuclear cells were isolated from healthy individuals after in- clude acquisition of class II from traditional APC. We compared formed consent in green-capped, heparinized tubes by Ficoll-Hypaque (GE Healthcare) gradient centrifugation. CD19ϩ B cells were isolated using class II MHC synthesis in these clones to genetically identical CD19 microbeads (Miltenyi Biotec). Total CD4ϩ T cells were isolated via EBV-transformed B cell lines. This comparison allowed us to con- the CD4ϩ T cell negative isolation kit II (Miltenyi Biotec) and incubated trol for donor-to-donor variability in protein expression, enzyme with an excess volume of fluorochrome-labeled Abs against HLA-DR activity, and MHC haplotype.
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