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J Biol Chem, Vol. 275, Issue 10, 6733-6740, March 10, 2000

T Cells Activated by Zwitterionic Molecules Prevent Abscesses Induced by Pathogenic Bacteria*

Arthur O. TzianabosDagger §, Robert W. Finberg||, Ying WangDagger §, Melvin Chan||, Andrew B. OnderdonkDagger **, Harold J. JenningsDagger Dagger , and Dennis L. KasperDagger §§§

From the Dagger  Channing Laboratory, Brigham and Women's Hospital, Departments of § Medicine, ** Pathology, and §§ Microbiology and Molecular Genetics, || Division of Infectious Disease, Dana Farber Cancer Institute, Harvard Medical School Boston, Massachusetts 02115 and the Dagger Dagger  Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, K1A 0R6 Canada

Immunologic paradigms classify bacterial polysaccharides as T cell-independent antigens. However, these models fail to explain how zwitterionic polysaccharides (Zps) confer protection against intraabdominal abscess formation in a T cell-dependent manner. Here, we demonstrate that Zps elicit a potent CD4+ T cell response in vitro that requires available major histocompatibility complex class II molecules on antigen-presenting cells. Specific chemical modifications to Zps show that: 1) the activity is specific for carbohydrate structure, and 2) the proliferative response depends upon free amino and carboxyl groups on the repeating units of these polysaccharides. Peptides synthesized to mimic the zwitterionic charge motif associated with Zps also exhibited these biologic properties. Lysine-aspartic acid (KD) peptides with more than 15 repeating units stimulated CD4+ T cells in vitro and conferred protection against abscesses induced by bacteria such as Bacteroides fragilis and Staphylococcus aureus. Evidence for the biologic importance of T cell activation by these zwitterionic polymers was provided when human CD4+ T cells stimulated with these molecules in vitro and adoptively transferred to rats in vivo conferred protection against intraabdominal abscesses induced by viable bacterial challenge. These studies demonstrate that bacterial polysaccharides with a distinct charge motif activate T cells and that this activity confers immunity to a distinct pathologic response to bacterial infection.

* This work was supported in part by NIAID, National Institutes of Health, Grants AI 34073 and AI 39576.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Channing Laboratory, 181 Longwood Ave., Boston, MA 02115. Tel.: 617-525-2610; Fax: 617-731-1541; E-mail: atzianabos@channing.harvard.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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