INFECTION AND IMMUNITY, Apr. 2005, p. 2184–2189 0019-9567/05/$08.00 0 doi:10.1128/IAI.73.4.2184–2189.2005 Copyright © 2005, American Society for Microbiology. All Rights Reserved.
Vol. 73, No. 4
Effect of B7-2 and CD40 Signals from Activated Antigen-Presenting Cells on the Ability of Zwitterionic Polysaccharides To Induce T-Cell Stimulation Tom Li Stephen,1† Marcus Niemeyer,2† Arthur O. Tzianabos,2 Martin Kroenke,1 Dennis L. Kasper,2,3 and Wiltrud M. Kalka-Moll1,2,4* Institute for Medical Microbiology, Immunology and Hygiene,1 and First Department of Medicine,4 University of Cologne, Germany, and Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital,2 and Department of Microbiology and Molecular Genetics,3 Harvard Medical School, Boston, Massachusetts Received 3 September 2004/Accepted 25 October 2004
Carbohydrates have been thought to stimulate immune responses independently of T cells; however, zwitterionic polysaccharides (ZPSs) from the capsules of some bacteria elicit potent CD4 -T-cell responses in vivo and in vitro. We demonstrated that HLA-DR on professional antigen-presenting cells (APCs) is required for ZPS-induced T-cell proliferation in vitro (15). Recently, it was shown that ZPSs are processed to lowmolecular-weight carbohydrates by a nitric oxide-mediated mechanism in endosomes and locate in the major histocompatibility complex class II pathway (5, 15). The effect of the ZPS-mediated expression of HLA-DR and costimulatory molecules on the APC and T-cell engagement and subsequent T-cell activation has not been elucidated. Herein, we report that ZPS-mediated induction of HLA-DR-surface expression and T-cell proliferation are maximally enhanced after incubation of APCs for 8 h with ZPS. Treatment of APCs with baﬁlomycin A inhibits the up-regulation of ZPS-mediated HLA-DR surface expression and leads to inhibition of T-cell proliferation. Monoclonal antibodies (MAbs) to the costimulatory molecules B7-2 and CD40L speciﬁcally block ZPS-mediated T-cell activation, while a MAb to B7-1 does not. Surface expression of B7-2 and B7-1 but not of CD40 is maximally enhanced at 8 to 16 h of treatment of APCs with ZPS. The results demonstrate that the cellular immune response to ZPS depends on the translocation of HLA-DR to the cell surface and requires costimulation via B7-2 and CD40 on activated APCs. The implication is that activation of ZPS-speciﬁc T cells requires an orchestrated arrangement of both presenting and costimulatory molecules to form an immunological synapse. Most pathogenic extracellular bacteria produce large-molecular-mass surface polysaccharides, usually in the form of a capsule that coats the bacterial cell surface. The classiﬁcation of polysaccharides as T-cell-independent type 2 (TI-2) antigens is based on the lack of T-cell-dependent responses to these typically negatively charged or uncharged molecules (12, 13). In view of their immunogenic characteristics, bacterial zwitterionic polysaccharides (ZPSs) isolated from strains of Bacteroides fragilis, Staphylococcus aureus, and Streptococcus pneumoniae type 1 represent an unusual group of bacterial carbohydrates. ZPSs have unique immunological properties: molecules as small as 17 kDa elicit a potent CD4 -T-cell response in vitro and in vivo (16). Structure-function studies have shown that the proliferative response of T cells depends on free amino (positively charged) and carboxyl or phosphate groups (negatively charged) on each repeating unit (31, 32). The mediation of proliferation of human T cells in vitro is characterized by a requirement for direct interaction of T cells with HLA-DR-bearing antigen-presenting cells (APCs). ZPSs colocalize with HLA-DR in compartments of the endocytic pathway and on the cell surface (15). They are processed to low-molecular-weight carbohydrates by a nitric-oxide-dependent mechanism in endosomes and bind to major histocompatibility complex class II (MHC-II) inside APCs (5). Nuclear magnetic...
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