IFN-γ-producing CD4+ T cells promote generation of protective germinal center-derived IgM+ B cell memory against Salmonella Typhi

J Immunol. 2014 Jun 1;192(11):5192-200. doi: 10.4049/jimmunol.1302526. Epub 2014 Apr 28.


Abs play a significant role in protection against the intracellular bacterium Salmonella Typhi. In this article, we investigated how long-term protective IgM responses can be elicited by a S. Typhi outer-membrane protein C- and F-based subunit vaccine (porins). We found that repeated Ag exposure promoted a CD4(+) T cell-dependent germinal center reaction that generated mutated IgM-producing B cells and was accompanied by a strong expansion of IFN-γ-secreting T follicular helper cells. Genetic ablation of individual cytokine receptors revealed that both IFN-γ and IL-17 are required for optimal germinal center reactions and production of porin-specific memory IgM(+) B cells. However, more profound reduction of porin-specific IgM B cell responses in the absence of IFN-γR signaling indicated that this cytokine plays a dominant role. Importantly, mutated IgM mAbs against porins exhibited bactericidal capacity and efficiently augmented S. Typhi clearance. In conclusion, repeated vaccination with S. Typhi porins programs type I T follicular helper cell responses that contribute to the diversification of B cell memory and promote the generation of protective IgM Abs.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • Female
  • Germinal Center / immunology*
  • Germinal Center / pathology
  • Humans
  • Immunoglobulin M / immunology*
  • Immunologic Memory*
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology*
  • Male
  • Mice
  • Mice, Knockout
  • Salmonella Vaccines / genetics
  • Salmonella Vaccines / immunology
  • Salmonella typhi / immunology*
  • Typhoid Fever / genetics
  • Typhoid Fever / immunology
  • Typhoid Fever / pathology
  • Typhoid Fever / prevention & control


  • IFNG protein, human
  • Immunoglobulin M
  • Salmonella Vaccines
  • Interferon-gamma