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Berylliosis Candidates for Intervention in Chronic and Anti-LFA-1

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Berylliosis Candidates for Intervention in Chronic and Anti-LFA-1 The Journal of Immunology Activation Pathways Implicate Anti-HLA-DP and Anti-LFA-1 Antibodies as Lead Candidates for Intervention in Chronic Berylliosis1 Yuan K. Chou,2*§ David M. Edwards,2* Andrew D. Weinberg,¶ Arthur A. Vandenbark,*‡§ Brian L. Kotzin,ʈ Andrew P. Fontenot,ʈ and Gregory G. Burrows3*† CD4؉ T cells play a key role in granulomatous inflammation in the lung of patients with chronic beryllium disease. The goal of this study was to characterize activation pathways of beryllium-responsive bronchoalveolar lavage (BAL) CD4؉ T cells from chronic beryllium disease patients to identify possible therapeutic interventional strategies. Our results demonstrate that in the -presence of APCs, beryllium induced strong proliferation responses of BAL CD4؉ T cells, production of superoptimal concen trations of secreted proinflammatory cytokines, IFN-␥, TNF-␣,and IL-2, and up-regulation of numerous T cell surface markers that would promote T-T Ag presentation. Ab blocking experiments revealed that anti-HLA-DP or anti-LFA-1 Ab strongly reduced proliferation responses and cytokine secretion by BAL CD4؉ T cells. In contrast, anti-HLA-DR or anti-OX40 ligand Ab mainly affected beryllium-induced proliferation responses with little impact on cytokines other than IL-2, thus implying that nonprolif- erating BAL CD4؉ T cells may still contribute to inflammation. Blockade with CTLA4-Ig had a minimal effect on proliferation and cytokine responses, confirming that activation was independent of B7/CD28 costimulation. These results indicate a prominent role for HLA-DP and LFA-1 in BAL CD4؉ T cell activation and further suggest that specific Abs to these molecules could serve as a possible therapy for chronic beryllium disease. The Journal of Immunology, 2005, 174: 4316–4324. etailed characterization of resident T cells in tissues un- extremely vague, and in the majority of cases a consensus is far dergoing chronic inflammation presents a number of dif- from being established. D ficulties, not the least being the inaccessibility of the Chronic beryllium disease (CBD)4 is an occupational disease target organ. T cells involved in autoimmune disease of the CNS caused by exposure to the metal beryllium (molecular weight ϭ 9), (multiple sclerosis) and pancreas (type 1 diabetes) present extreme characterized by the formation of noncaseating granuloma and examples of this inaccessibility (1, 2). In addition, studies of mononuclear cell infiltration into the lung (8, 9). Immunological chronic inflammation and the characterization of the molecular studies have suggested that CD4ϩ T cells are important in the players involved have primarily focused on protein-derived pep- initiation and perpetuation of the beryllium-induced chronic in- tide Ags. However, T cell activation and pathogenesis can also be flammation (10, 11). Recognition of beryllium by CD4ϩ T cells in triggered by a wide variety of low molecular weight Ags, including CBD patients appears to involve certain HLA class II molecules, metals, frequently resulting in allergic hyperreactivity (3, 4) and and specific HLA-DP molecules have been associated with beryl- the ability of metals to induce T cell activation in a MHC-restricted lium sensitization and CBD severity (12–14). Beryllium-specific manner has been clearly established (5). Although several inter- CD4ϩ T cells have been found to express a Th1-type phenotype in esting models explaining this metal-induced activation of T cells response to beryllium sulfate (BeSO4) (15, 16), and nearly all have been proposed, a detailed understanding of the precise nature bronchoalveolar lavage (BAL) T cells from patients with CBD of the epitope recognized by metal-specific T cells remains in al- exhibit an effector memory cell phenotype (17–19). The develop- most all cases unknown (6, 7). Furthermore, the detailed immu- ment of granulomatous inflammation is associated with the accu- nological characteristics defining the T cell response to metals is mulation of activated CD4ϩ T cells in the BAL (20). The majority of beryllium-specific CD4ϩ T cells are compartmentalized in the lung, with up to 20–30% of the BAL CD4ϩ T cells being beryl- Departments of *Neurology, †Biochemistry and Molecular Biology, and ‡Molecular lium specific and expressing Th1-type cytokines upon beryllium Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97239; §Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR exposure in culture (17). In a number of CBD patients studied, the 97207; ¶Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, T cells showed oligoclonal expansion with particular TCRs spe- ʈ Providence Portland Medical Center, Portland, OR 97213; and Department of Med- cific for CBD (21), and analysis of TCR expression on BAL CD4ϩ icine and Immunology, University of Colorado Health Sciences Center, Denver, CO 80206 T cells has revealed the presence of TCR motifs specific for be- Received for publication October 8, 2004. Accepted for publication January 24, 2005. ryllium-reactive T cells (22). We have chosen to study CBD and ϩ The costs of publication of this article were defrayed in part by the payment of page beryllium-induced molecular changes in CD4 T cells both as a charges. This article must therefore be hereby marked advertisement in accordance model of metal-induced T cell activation in the lung and as an with 18 U.S.C. Section 1734 solely to indicate this fact. opportunity to characterize resident CD4ϩ T cells from tissues 1 This work was supported by the National Institutes of Health Grants ES10554 (to undergoing chronic inflammation. Our long-term goal is to map G.G.B), HL062410, and P01ES011810 (to A.P.F.) and by the Department of Neu- rology, OHSU, and the Veterans Affairs Medical Center (Portland, OR). the cascade of events that control the resident T cell populations’ 2 Y.K.C. and D.M.E. contributed equally to this project. 3 Address correspondence and reprint requests to Dr. Gregory G. Burrows, Depart- 4 Abbreviations used in this paper: CBD, chronic beryllium disease; AMLR, autolo- ment of Neurology, UHS-46, Oregon Health & Science University, 3181 SW Sam gous MLR; BAL, bronchoalveolar lavage; CBA, cytokine bead array; MOG, myelin Jackson Park Road, Portland, OR 97239. E-mail address: address:[email protected] oligodendrocyte glycoprotein; OX40L, OX40 ligand; SI, stimulation index. Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 4317 behavior as a means of obtaining new insights focused on how to the same concentration range as that used for autologous APCs. As irrel- prevent this chronic inflammatory and eventually debilitating evant Ag controls, NiSO4 (Sigma-Aldrich) and the myelin oligodendrocyte glycoprotein (MOG) 35–55 peptide (New England Peptide) were used. disease. ϩ Morphological features of BAL CD4 T cell activation in the culture, with With regard to Ag-specific T cell activation, naive T cells appear either EBV-transformed autologous APCs or DAP3(DP2)-transfected ␮ to require two signaling events, TCR engagement with Ag/MHC APCs upon stimulation with 10 M BeSO4, were studied by microscopy and a second costimulatory signal, which is most frequently me- (Leica Microsystems). diated by the engagement of CD28 on the T cell with its ligands Cell surface marker phenotyping B7-1 or B7-2, on APCs (23, 24). The BAL beryllium-specific ϩ CD4ϩ T cells are effector memory cells that proliferate and secrete BAL CD4 T cell surface marker phenotyping in an unstimulated state was followed by stimulation with 10 ␮M BeSO at 24, 48, 72, 96, 120, and cytokines after TCR engagement without an absolute requirement 4 144 h in the presence of EBV-transformed autologous APCs and IL-2. All for CD28-mediated costimulation (25). This result suggested either Abs were purchased from BD Pharmingen and BD Biosciences, with the no dependence on costimulation or the involvement of a different exception of anti-CD28 (CALTAG Laboratories) and anti-OX40L (R&D costimulation pathway such as OX40/OX40 ligand (OX40L). Systems). All markers were costained with either CD4-FITC or CD4-PE OX40 (CD134), a membrane-bound member of the TNFR super- (clone RPA-T4; catalogues nos. 555346 and 555347, respectively). The ϩ surface markers were stained with the following mAbs: CD3-PE (clone family, is expressed primarily on activated CD4 T cells (26). UCHT1; catalogue no. 555333), CD8-PE (clone RPA-T8; catalogue no. Following engagement of OX40 with OX40L expressed on the 555367), CD45RO-FITC (clone UCHL1; catalogue no.555492), APC, OX40 delivers a costimulatory signal that leads to potent, ␣␤TCR-PE (clone T10B9.1A-31; catalogue no. 555548), CD25-PE (clone proinflammatory effects (27, 28). However, whether or not human M-A251; catalogue no.555432), CD69 (clone FN50; catalogue no. beryllium-specific CD4ϩ T cells expressed OX40 and, if so, 555529), CD134-PE (OX40) (clone L106; catalogue no. 340420), OX40L (TNFSF4) (clone 159403; catalogue no. MAB10541), CD28 (clone 15E8; whether the OX40/OX40L costimulatory pathway could play a catalogue no. MHCD2800–4), CD152-PE (CTLA-4) (clone BNI3; cata- ϩ role in beryllium-induced CD4 T cell activation has not been logue no.555853), CD80 (B7-1) (clone L307.4; catalogue no. 557227), explored previously. CD86 (B7-2) (clone 2331; catalogue no. 555658), CD50 (ICAM-3) (clone In the current study, we evaluated a beryllium-reactive T cell TU41; catalogue no. 555957), CD11a (LFA-1) (clone HI111; catalogue no. 555382), HLA-DR (clone L243, catalogue no. 347360), HLA-DP (clone line from the BAL of a CBD patient for the level and the duration B7/21; catalogue no. 347730), and HLA-DQ (clone SK10; catalogue no. of T cell proliferation and cytokine secretion, MHC restriction, and 347450). EBV-transformed APCs and DP2- or DP4-transfected APCs were changes in the expression of T cell adhesion molecules, activation stained appropriately with CD-19-PE (clone HIB19; catalogue no.
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