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

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 andStaphylococcus 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 vitroand 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.

[1]  D. Kasper,et al.  Structure-function relationships for polysaccharide-induced intra-abdominal abscesses , 1994, Infection and immunity.

[2]  D. Kasper,et al.  IL-2 mediates protection against abscess formation in an experimental model of sepsis. , 1999, Journal of immunology.

[3]  M. Fridkis-Hareli,et al.  Promiscuous binding of synthetic copolymer 1 to purified HLA-DR molecules , 1997, Journal of immunology.

[4]  P. Brennan,et al.  CD1-restricted T cell recognition of microbial lipoglycan antigens. , 1995, Science.

[5]  D. Kasper,et al.  Structural features of polysaccharides that induce intra-abdominal abscesses. , 1993, Science.

[6]  S. Reid,et al.  A phosphorylcholine-containing filarial nematode-secreted product disrupts B lymphocyte activation by targeting key proliferative signaling pathways. , 1997, Journal of immunology.

[7]  R. Holmdahl,et al.  T cell recognition of carbohydrates on type II collagen , 1994, The Journal of experimental medicine.

[8]  D. Kasper,et al.  Polysaccharide-mediated protection against abscess formation in experimental intra-abdominal sepsis. , 1995, The Journal of clinical investigation.

[9]  E. Unanue,et al.  Glycopeptides bind MHC molecules and elicit specific T cell responses. , 1993, Journal of immunology.

[10]  M. Bonneville,et al.  Stimulation of human gamma delta T cells by nonpeptidic mycobacterial ligands. , 1994, Science.

[11]  T. Brodie,et al.  Galactose oxidation in the design of immunogenic vaccines. , 1992, Science.

[12]  B. Polk,et al.  Bacteroides fragilis subspecies in clinical isolates. , 1977, Annals of internal medicine.

[13]  A. Ulmer,et al.  Structural Elucidation and Monokine-inducing Activity of Two Biologically Active Zwitterionic Glycosphingolipids Derived from the Porcine Parasitic Nematode Ascaris suum * , 1998, The Journal of Biological Chemistry.

[14]  J. I. Jones Advances in Organic Chemistry , 1965, Nature.

[15]  J. Bartlett,et al.  Protective efficacy of immunization with capsular antigen against experimental infection with Bacteroides fragilis. , 1979, The Journal of infectious diseases.

[16]  R. Finberg,et al.  Human γδ+ T cells respond to mycobacterial heat-shock protein , 1989, Nature.

[17]  S. Porcelli,et al.  CDlb restricts the response of human CD4−8−T lymphocytes to a microbial antigen , 1992, Nature.

[18]  B. Lindberg,et al.  Structural studies of the capsular polysaccharide from Streptococcus pneumoniae type 1. , 1980, Carbohydrate research.

[19]  J. Brisson,et al.  The capsular polysaccharide of Bacteroides fragilis comprises two ionically linked polysaccharides. , 1992, The Journal of biological chemistry.

[20]  M. Apicella,et al.  T-cell modulation of the murine antibody response to Neisseria meningitidis group A capsular polysaccharide , 1988, Infection and immunity.

[21]  D. Kasper,et al.  Mitogenic activity of purified capsular polysaccharide A from Bacteroides fragilis: differential stimulatory effect on mouse and rat lymphocytes in vitro. , 1999, Journal of immunology.

[22]  Yoshimasa Tanaka,et al.  Direct presentation of nonpeptide prenyl pyrophosphate antigens to human γδ T cells , 1995 .

[23]  J. Bartlett,et al.  Microbial synergy in experimental intra-abdominal abscess , 1976, Infection and immunity.

[24]  C. Taylor,et al.  T-cell modulation of the antibody response to bacterial polysaccharide antigens , 1989, Infection and immunity.

[25]  M. Harnett,et al.  Induction of signalling anergy via the T‐cell receptor in cultured Jurkat T cells by pre‐exposure to a filarial nematode secreted product , 1998, Parasite immunology.

[26]  J. Bartlett,et al.  The capsular polysaccharide of Bacteroides fragilis as a virulence factor: comparison of the pathogenic potential of encapsulated and unencapsulated strains. , 1977, The Journal of infectious diseases.

[27]  O. Avery,et al.  CHEMOIMMUNOLOGICAL STUDIES ON THE SOLUBLE SPECIFIC SUBSTANCE OF PNEUMOCOCCUS , 1933, The Journal of experimental medicine.

[28]  S. Porcelli,et al.  Recognition of a lipid antigen by GDI-restricted αβ+ T cells , 1994, Nature.

[29]  M. Sela,et al.  Binding of copolymer 1 and myelin basic protein leads to clustering of class II MHC molecules on antigen-presenting cells. , 1997, International immunology.

[30]  D. Kasper,et al.  Structural characteristics of polysaccharides that induce protection against intra-abdominal abscess formation , 1994, Infection and immunity.

[31]  F. Sallusto,et al.  Major Histocompatibility Complex–independent Recognition of a Distinctive Pollen Antigen, Most Likely a Carbohydrate, by Human CD8+ α/β T Cells , 1997, The Journal of experimental medicine.

[32]  R. Finberg,et al.  Decay-accelerating factor expression on either effector or target cells inhibits cytotoxicity by human natural killer cells. , 1992, Journal of immunology.

[33]  B. Polk,et al.  Isolation and identification of encapsulated strains of Bacteroides fragilis. , 1977, The Journal of infectious diseases.

[34]  R. Dwek,et al.  Recognition of carbohydrate by major histocompatibility complex class I- restricted, glycopeptide-specific cytotoxic T lymphocytes , 1994, The Journal of experimental medicine.

[35]  T. Tosteson,et al.  Effects of chain length on the immunogenicity in rabbits of group B Streptococcus type III oligosaccharide-tetanus toxoid conjugates. , 1992, The Journal of clinical investigation.

[36]  D. Kasper,et al.  Immunochemical characterization of two surface polysaccharides of Bacteroides fragilis , 1991, Infection and immunity.

[37]  M. Sela,et al.  Synthetic Copolymer I and Myelin Basic Protein Do Not Require Processing Prior to Binding to Class II Major Histocompatibility Complex Molecules on Living Antigen-Presenting Cells , 1995 .

[38]  H. Grey,et al.  MHC interaction and T cell recognition of carbohydrates and glycopeptides. , 1992, Journal of immunology.

[39]  G. Pier,et al.  In vitro T cell-mediated killing of Pseudomonas aeruginosa. II. The role of macrophages and T cell subsets in T cell killing. , 1985, Journal of immunology.

[40]  J. Brisson,et al.  Structural elucidation of two capsular polysaccharides from one strain of Bacteroides fragilis using high-resolution NMR spectroscopy. , 1992, Biochemistry.

[41]  E. Unanue,et al.  Effects of pH and polysaccharides on peptide binding to class II major histocompatibility complex molecules. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[42]  T. Nutman,et al.  Phosphocholine-containing antigens of Brugia malayi nonspecifically suppress lymphocyte function. , 1990, The American journal of tropical medicine and hygiene.