Polysaccharide-specific memory B cells generated by conjugate vaccines in humans conform to the CD27+IgG+ isotype-switched memory B Cell phenotype and require contact-dependent signals from bystander T cells activated by bacterial proteins to differentiate into plasma cells.
The polysaccharides (PS) surrounding encapsulated bacteria are generally unable to activate T cells and hence do not induce B cell memory (BMEM). PS conjugate vaccines recruit CD4(+) T cells via a carrier protein, such as tetanus toxoid (TT), resulting in the induction of PS-specific BMEM. However, the requirement for T cells in the subsequent activation of the BMEM at the time of bacterial encounter is poorly understood, despite having critical implications for protection. We demonstrate that the PS-specific BMEM induced in humans by a meningococcal serogroup C PS (Men C)-TT conjugate vaccine conform to the isotype-switched (IgG(+)CD27(+)) rather than the IgM memory (IgM(+)CD27(+)) phenotype. Both Men C and TT-specific BMEM require CD4(+) T cells to differentiate into plasma cells. However, noncognate bystander T cells provide such signals to PS-specific BMEM with comparable effect to the cognate T cells available to TT-specific BMEM. The interaction between the two populations is contact-dependent and is mediated in part through CD40. Meningococci drive the differentiation of the Men C-specific BMEM through the activation of bystander T cells by bacterial proteins, although these signals are enhanced by T cell-independent innate signals. An effect of the TT-specific T cells activated by the vaccine on unrelated BMEM in vivo is also demonstrated. These data highlight that any protection conferred by PS-specific BMEM at the time of bacterial encounter will depend on the effectiveness with which bacterial proteins are able to activate bystander T cells. Priming for T cell memory against bacterial proteins through their inclusion in vaccine preparations must continue to be pursued.
School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, United Kingdom;
Edward T
ET
Clarke
Neil A
NA
Williams
Jamie
J
Findlow
Ray
R
Borrow
Robert S
RS
Heyderman
Adam
A
Finn
D017951:Antigen Presentation; D000942:Antigens, Bacterial / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D024201:Bystander Effect / Q000276:immunology*; D006801:Humans; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000032:analysis; D007156:Immunologic Memory / Q000276:immunology*; D016130:Immunophenotyping; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D038041:Lymphopoiesis / Q000276:immunology*; D018448:Models, Immunological; D038542:Neisseria meningitidis, Serogroup C / Q000276:immunology*; D014066:Palatine Tonsil / Q000276:immunology; D010950:Plasma Cells / Q000166:cytology*; D011135:Polysaccharides, Bacterial / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013745:Tetanus Toxoid / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis; D018074:Vaccines, Conjugate / Q000276:immunology
D000942:Antigens, Bacterial; D007074:Immunoglobulin G; D011135:Polysaccharides, Bacterial; D011947:Receptors, Antigen, B-Cell; D013745:Tetanus Toxoid; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D018074:Vaccines, Conjugate; C037676:meningococcal group C polysaccharide; C052181:meningococcal group C polysaccharide-tetanus toxoid conjugate