Polysaccharide A from the capsule of Bacteroides fragilis induces clonal CD4+ T cell expansion

Area of Science:

• Immunology
• Microbial Pathogenesis
• T Cell Biology

Background:

• The role of Major Histocompatibility Complex class II (MHCII) in antigen presentation has historically focused on peptide antigens.
• Previous research demonstrated MHCII's capacity to present processed fragments of zwitterionic capsular polysaccharides to T cells.
• Polysaccharide A (PSA) from Bacteroides fragilis is known to activate CD4(+) T cells, vital for maintaining immune homeostasis.

Purpose of the Study:

• To investigate the nature of T cell recognition of the polysaccharide-MHCII complex.
• To characterize the phenotype of CD4(+) T cells activated by polysaccharide antigens.
• To elucidate the T cell receptor (TCR) repertoire involved in PSA-MHCII interactions.

Main Methods:

• Utilized next-generation sequencing to analyze the αβT cell receptor repertoire of CD4(+) T cells.
• Compared T cells from mice immunized with PSA, protein antigen, and non-immunized controls.
• Analyzed complementarity-determining region 3 (CDR3) loop sequences for clonal expansion and motif preferences.

Main Results:

• PSA immunization led to the clonal expansion of a specific subset of suppressive CD4(+)CD45RB(low) effector/memory T cells.
• TCR sequencing revealed a lack of specific variable β and joining region usage and average CDR3 loop length.
• A preference for a zwitterionic motif within CDR3 loop sequences was observed, correlating with PSA's structural requirements for T cell activation.

Conclusions:

• PSA elicits a clonal and specific CD4(+) T cell response, challenging the peptide-centric view of MHCII presentation.
• The findings support a model where polysaccharide antigens engage specific TCRs, characterized by dual-charged CDR3 loops interacting with zwitterionic PSA.
• This mechanism highlights a distinct pathway for T cell activation by non-peptide antigens, contributing to immune regulation and homeostasis.