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 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.
Tzianabos
A O
AO
Channing Laboratory, Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School Boston, Massachusetts 02115, USA. atzianabos@channing.harvard.edu
Finberg
R W
RW
Wang
Y
Y
Chan
M
M
Onderdonk
A B
AB
Jennings
H J
HJ
Kasper
D L
DL
D000038:Abscess / Q000517:prevention & control*; D000818:Animals; D001441:Bacteroides fragilis / Q000276:immunology; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D010455:Peptides / Q000494:pharmacology; D011135:Polysaccharides, Bacterial / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013296:Streptococcus pneumoniae / Q000276:immunology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D010455:Peptides; D011135:Polysaccharides, Bacterial