Human B cells differentiate into granzyme B-secreting cytotoxic B lymphocytes upon incomplete T-cell help

Immunol Cell Biol. 2012 Apr;90(4):457-67. doi: 10.1038/icb.2011.64. Epub 2011 Aug 2.

Abstract

Recently, CD4(+) T helper cells were shown to induce differentiation of human B cells into plasma cells by expressing interleukin (IL-)21 and CD40 ligand (CD40L). In the present study we show, that in the absence of CD40L, CD4(+) T cell-derived IL-21 induces differentiation of B cells into granzyme B (GzmB)-secreting cytotoxic cells. Using fluorescence-activated cell sorting (FACS) analysis, ELISpot and confocal microscopy, we demonstrate that CD4(+) T cells, activated via their T-cell receptor without co-stimulation, can produce IL-21, but do not express CD40L and rapidly induce GzmB in co-cultured B cells in an IL-21 receptor-dependent manner. Of note, we confirmed these results with recombinant reagents, highlighting that CD40L suppresses IL-21-induced GzmB induction in B cells in a dose-dependent manner. Surprisingly, although GzmB-secreting B cells did not express perforin, they were able to transfer active GzmB to tumor cell lines, thereby effectively inducing apoptosis. In contrast, no cytotoxic effects were found when effector B cells were activated with IL-2 instead of IL-21 or when target cells were cultured with IL-21 alone. Our findings suggest GzmB(+) cytotoxic B cells may have a role in early cellular immune responses including tumor immunosurveillance, before fully activated, antigen-specific cytotoxic T cells are on the spot. CD40 ligand determines whether IL-21 induces differentiation of B cells into plasma cells or into granzyme B-secreting cytotoxic cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / cytology*
  • B-Lymphocytes / metabolism
  • CD40 Ligand
  • Cell Differentiation / immunology*
  • Cells, Cultured
  • Granzymes / metabolism*
  • Humans
  • Immunity, Cellular
  • Interleukin-2 / pharmacology
  • Interleukins / pharmacology
  • T-Lymphocytes, Helper-Inducer / immunology*

Substances

  • Interleukin-2
  • Interleukins
  • CD40 Ligand
  • Granzymes
  • interleukin-21