Cytokine-producing effector B cells regulate type 2 immunity to H. polygyrus.

Trudeau Institute, Saranac Lake, NY 12983, USA.
Immunity (Impact Factor: 19.8). 03/2009; 30(3):421-33. DOI: 10.1016/j.immuni.2009.01.006
Source: PubMed

ABSTRACT Immunity to the intestinal parasite Heligomosomoides polygyrus is dependent on the successful generation of T helper 2 (Th2) memory cells. We showed that B cells contribute to immunity against H. polygyrus by producing antibody (Ab) and by promoting expansion and differentiation of primary and memory Th2 cells. We also demonstrated that cytokine-producing effector B cells were essential for effective immunity to H. polygyrus. Tumor necrosis factor alpha production by B cells was necessary for sustained Ab production, whereas interleukin 2 production by B cells was necessary for Th2 cell expansion and differentiation. These results show that B cells mediate protection from pathogens not only by presenting antigen and secreting antibody but also by producing cytokines that regulate the quality and magnitude of humoral and cellular immune responses.

1 Bookmark
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The nematode Heligmosomoides polygyrus is an excellent model for intestinal helminth parasitism. Infection in mice persists for varying lengths of time in different inbred strains, with CBA and C57BL/6 mice being fully susceptible, BALB/c partially so and SJL able to expel worms within 2-3 weeks of infection. We find that resistance correlates not only with the adaptive Th2 response, including IL-10 but with activation of innate lymphoid cell and macrophage populations. In addition, the titer and specificity range of the serum antibody response is maximal in resistant mice. In susceptible strains, Th2 responses were found to be counterbalanced by IFN-γ-producing CD4(+) and CD8(+) cells, but these are not solely responsible for susceptibility as mice deficient in either CD8(+) T cells or IFN-γ remain unable to expel the parasites. Foxp3(+) Treg numbers were comparable in all strains, but in the most resistant SJL strain, this population does not upregulate CD103 in infection, and in the lamina propria the frequency of Foxp3(+)CD103(+) T cells is significantly lower than in susceptible mice. The more resistant SJL and BALB/c mice develop macrophage-rich IL-4Rα-dependent Type 2 granulomas around intestinal sites of larval invasion, and expression of alternative activation markers Arginase-1, Ch3L3 (Ym1) and RELM-α within the intestine and the peritoneal lavage was also strongly correlated with helminth elimination in these strains. Clodronate depletion of phagocytic cells compromises resistance of BALB/c mice and slows expulsion in the SJL strain. Thus, Type 2 immunity involves IL-4Rα-dependent innate cells including but not limited to a phagocyte population, the latter likely involving the action of specific antibodies.Immunology and Cell Biology advance online publication, 4 February 2014; doi:10.1038/icb.2013.109.
    Immunology and Cell Biology 02/2014; · 3.93 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dynamic interactions between CD4(+) T cells and B cells are needed for humoral immunity and CD4(+) T cell memory. It is not known whether B cells are needed early on to induce the formation of memory precursor cells or are needed later to sustain memory cells. In this study, primary and memory CD4(+) T cells responses were followed in wild-type mice that were depleted of mature B cells by anti-CD20 before or different times after acute lymphocytic choriomeningitis virus infection. The Ab treatment led to a 1000-fold reduction in B cell number that lasted 6 wk. Primary virus-specific CD4(+) Th1 cells were generated in B cell-depleted mice; however, there was a decrease in the CD4(+)Ly6C(lo)Tbet(+) memory precursor population and a corresponding 4-fold reduction in CD4(+) memory cell number. Memory T cells showed impaired cytokine production when they formed without B cells. B cell depletion had no effect on established memory populations. During disseminating virus infection, B cell depletion led to sustained weight loss and functional exhaustion of CD4(+) and CD8(+) T cells, and prevented mice from resolving the infection. Thus, B cells contribute to the establishment and survival of memory CD4(+) T cells post-acute infection and play an essential role in immune protection against disseminating virus infection.
    The Journal of Immunology 02/2014; 192(4):1597-1608. · 5.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: B lymphocytes are generally recognized for their potential to mediate humoral immunity by producing different antibody isotypes and being involved in opsonization and complement fixation. Nevertheless, the non-classical, antibody-independent immune potential of B cell subsets has attracted much attention especially in the past decade. These B cells can release a broad variety of cytokines (such as IL-2, IL-4, IL-6, IL-10, IL-17, IFN-α, IFN-γ, TNF-α, TGF-β, LT), and can be classified into distinct subsets depending on the particular cytokine profile, thus emerging the concept of cytokine-producing B cell subsets. Although there is still controversy surrounding the key cell surface markers, intracellular factors and cellular origins of cytokine-producing B cell subsets, accumulating evidence indicates that these B cells are endowed with great potential to regulate both innate and adaptive arms of immune system though releasing cytokines. On the one hand, they promote immune responses through mounting Th1/Th2/Th17 and neutrophil response, inducing DC maturation and formation of lymphoid structures, increasing NK cell and macrophage activation, enhancing development of themselves and sustaining antibody production. On the other hand, they can negatively regulate immune responses by suppressing Th cell responses, inhibiting Tr1 cell and Foxp3(+) Treg differentiation, impairing APC function and pro-inflammatory cytokine release by monocytes, and inducing CD8(+) T cell anergy and CD4(+) T cell apoptosis. Therefore, cytokine-producing B cell subsets have multifunctional functions in health and diseases, playing pathologic as well as protective roles in autoimmunity, infection, allergy, and even malignancy. In this review, we revisit the history of discovering cytokine-producing B cells, describe the identification of cytokine-producing B cell subsets, introduce the origins of cytokine-producing B cell subsets as well as molecular and cellular mechanisms for their differentiation, and summarize the recent progress made toward understanding the unexpectedly complex and potentially opposing roles of cytokine-producing B cells in immunological disorders.
    Journal of Autoimmunity 04/2014; · 8.15 Impact Factor


Available from