Polysaccharide A from the Capsule of Bacteroides fragilis Induces Clonal CD4+ T Cell Expansion

• Published in: The Journal of biological chemistry Vol. 290; no. 8; pp. 5007 - 5014
• Main Authors: Johnson, Jenny L., Jones, Mark B., Cobb, Brian A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.02.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Bacterial Capsules - chemistry; Bacteroides fragilis; Bacteroides fragilis - chemistry; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; Complementarity Determining Regions - immunology; Glycobiology; Immunologic Memory - drug effects; Immunology; Lymphocyte; Lymphocyte Activation - drug effects; Major Histocompatibility Complex (MHC); Mice; Polysaccharide; Polysaccharides, Bacterial - chemistry; Polysaccharides, Bacterial - pharmacology; Receptors, Antigen, T-Cell, alpha-beta - immunology; Glycobiology; Immunology; Major Histocompatibility Complex (MHC); Lymphocyte; Polysaccharide
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.621771

For 3 decades, the view of MHCII-dependent antigen presentation has been completely dominated by peptide antigens despite our 2004 discovery in which MHCII was shown to present processed fragments of zwitterionic capsular polysaccharides to T cells. Published findings further demonstrate that polysaccharide A (PSA) from the capsule of Bacteroides fragilis is a potent activator of CD4+ T cells and that these T cells have important biological functions, especially in the maintenance of immunological homeostasis. However, little is known about the nature of T cell recognition of the polysaccharide-MHCII complex or the phenotype of the resulting activated cells. Here, we use next-generation sequencing of the αβT cell receptor of CD4+ T cells from mice stimulated with PSA in comparison with protein antigen simulation and non-immunized controls and found that PSA immunization induced clonal expansion of a small subset of suppressive CD4+CD45RBlow effector/memory T cells. Moreover, the sequences of the complementarity-determining region 3 (CDR3) loop from top clones indicate a lack of specific variable β and joining region use and average CDR3 loop length. There was also a preference for a zwitterionic motif within the CDR3 loop sequences, aligning well with the known requirement for a similar motif within PSA to enable T cell activation. These data support a model in which PSA, and possibly other T cell-dependent polysaccharide antigens, elicits a clonal and therefore specific CD4+ T cell response often characterized by pairing dual-charged CDR3 loop sequences with dual-charged PSA. Background: Zwitterionic polysaccharides activate CD4+ T cells via MHCII presentation. Results: Zwitterionic polysaccharides induce clonal expansion of a subset of anti-inflammatory CD4+ T cells preferentially carrying zwitterionic CDR3 loops. Conclusion: MHCII-presented polysaccharides are specifically recognized by CD4+ T cells with regulatory T cell activity. Significance: Zwitterionic polysaccharides are the first non-peptide MHCII-dependent antigens identified that induce clonal T cell expansion.