Peptide fragments presented in the context of MHC class II molecules are the typical antigens recognized by CD4+ T cells that express αβ-T-cell receptors. However, a paper published in Cell now reports that certain polysaccharides, when processed by antigen-presenting cells (APCs), can associate with MHC class II molecules and induce CD4+ T-cell responses.
Previous studies have shown that in rodent models of intra-abdominal abscess formation, abscesses form as a result of CD4+ T-cell activation by bacterial capsular polysaccharides that contain a repeating zwitterionic-charge motif — a repeating unit containing both positive and negative charges. As zwitterionic polysaccharide (ZPS)-induced activation of CD4+ T cells in vitro requires APC uptake of ZPS, as well as MHC class II molecules, Cobb et al. set out to investigate whether ZPS uses the conventional MHC class II antigen-presentation pathway.
Using confocal microscopy, polysaccharide A (PS-A) — a Bacteroides fragilis ZPS — was observed on the cell membrane and within APCs. In both locations, PS-A colocalized with MHC class II molecules. Uptake of PS-A by APCs was mediated by endocytosis, and colocalization of PS-A with MHC class II molecules involved fusion of exocytic vesicles with the endosomes, both characteristics of the conventional MHC class II antigen-presentation pathway.
Analysis of PS-A taken up by APCs indicated that the polysaccharide was catabolized after overnight culture. When studied in vitro, PS-A processing was only achieved by oxidizing agents such as O3. Oxidation was also shown to be important in vivo, because compared with wild-type animals, markedly fewer mice lacking inducible nitric oxide synthase (iNOS) developed abscesses when challenged with B. fragilis or PS-A in adjuvant. Further evidence that processed PS-A fragments bound to MHC class II molecules are responsible for CD4+ T-cell activation and abscess formation was provided by the observation that after overnight culture with PS-A, fragments of the ZPS could be detected bound to MHC class II molecules from wild-type APCs but not iNOS-deficient APCs.
This study, indicating that iNOS-dependent processing of ZPS antigens yields carbohydrate fragments that associate with MHC class II molecules and induce CD4+ T-cell responses, markedly increases the repertoire of pathogenic molecules that can stimulate T cells. The authors suggest that these observations might explain why some polysaccharide vaccines work so well and might provide new approaches to the design of vaccines for infectious diseases.
ORIGINAL RESEARCH PAPER
Cobb, B. A., Wang, Q., Tzianabos, A. O. & Kasper, D. L. Polysaccharide processing and presentation by the MHCII pathway. Cell 117, 677–687 (2004).
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Honey, K. Presenting a newly charged antigen. Nat Rev Immunol 4, 489 (2004). https://doi.org/10.1038/nri1399