Interleukin-4-Dependent Immunoglobulin G1 Isotype Switch in the Presence of a Polarized Antigen-Specific Th1-Cell Response to the Trypanosome Variant Surface Glycoprotein

Abstract

This study examines B-cell immunoglobulin (Ig) class-switching events in the context of parasite antigen-specific Th-cell responses in experimental African trypanosomiasis. Inbred mice were infected withTrypanosoma brucei rhodesiense, and the coordinate stimulation of Th-cell cytokine responses and B-cell responses to the trypanosome variant surface glycoprotein (VSG) was measured. The cytokines produced by T cells in response to VSG, at both the transcript and protein levels, were gamma interferon and interleukin-2 (IL-2) but not IL-4 or IL-5. Isotype profiles of antibodies specific for VSG showed that IgG1, IgG2a, and IgG3 switch responses predominated; no VSG-specific IgE responses were detected. To determine whether cryptic IL-4 responses played a role in promoting the unexpected IgG1 switch response, IL-4 knockout mice were infected; the cytokine responses and Ig isotype profiles of IL-4 knockout mice were identical to those of the wild-type control mice except for dramatically reduced IgG1 levels in response to VSG. Thus, these results revealed an IL-4-dependent component of the VSG-driven B-cell Cμ-to-Cγ1 switch. We speculate that an IL-4 response is mediated primarily by cells other than T lymphocytes since IL-4-secreting but parasite antigen-unresponsive, “background” cells were detected in all infected mice and since infected nude mice also displayed a detectable IgG1 switch response. Overall, our results suggest that B-cell clonal stimulation, maturation, and Ig class switching in African trypanosomiasis may be partially regulated by unusual mechanisms that do not include antigen-specific Th1 or Th2 cells.

Cytokines and antibody responses during Trypanosoma congolense infections in two inbred mouse strains that differ in resistance

“…These results clearly show that there was no correlation between the frequency of cytokine-secreting cells and the actual amount of cytokine secretion by the cells. This is consistent with the recent findings of Schopf et al (1998) that showed that although IL-4-secreting cells in the spleens of T. brucei rhodesiense-infected mice were readily demonstrable by ELISPOT, no detectable amount of IL-4 protein was measurable in culture fluids of splenocytes from these mice.…”

“…However, this possibility seems less likely since similar cultures of splenocytes from BALB/c mice produced significant amounts of IL-4 ( Figure 3a). Similar observation has been made in resistant B10.BR mice infected with T. brucei rhodesiense wherein IL-4-secreting cells were readily demonstrable in the spleens whereas no measurable amount of IL-4 was detected in splenocyte culture fluids even in the presence of blocking anti-IL-4 receptor antibodies (Schopf et al 1998). Similarly, although greater numbers of IL-4-than IFN-g-secreting splenocytes (approximate ratio, 2 : 1) were detected on day 6 in the BALB/c mice, the ratio of IL-4 to IFN-g protein secreted in culture was dramatically different (IL-4:IFN-g ¼ 1 : 85).…”

“…IL-4 has been shown to promote B cell growth and differentiation into antibody-secreting cells as well as switch from IgM and IgG1 antibody isotype (Finkelman & Holmes 1990). In mice infected with T. brucei rhodesiense, IL-4 derived from non-TH2 cells mediates the switch from IgM to IgG1 anti-VSG antibodies (Schopf et al 1998). IL-2 and IFN-g on the other hand promote cell-mediated immunity and production of IgG2a and IgG3 antibody isotypes (Finkelman & Holmes 1990, Boehm et al 1997, Metzger et al 1997.…”

Prospects for vaccination against pathogenic African trypanosomes

“…A major shift in this paradigm was provided by studies that demonstrated relative resistance to infection was linked functionally and genetically to VSG-specific CD4 + Th1 cell responses. [1][2][3][4][5][6] Further studies revealed that Th1 cells were a major source of the cytokine interferon-gamma (IFN-γ) that was linked to relative resistance 7 ; IFN-γ served to activate macrophages in host tissues, with the result that a number of cytotoxic factors are released that are capable of killing trypanosomes in a variant-nonspecific manner ( Figures 1 and 2). 6,[8][9][10][11] Thus, the ability to selectively induce Th1 cell responses to trypanosome antigens may have benefits for host resistance.…”

Infections With Extracellular Trypanosomes Require Control by Efficient Innate Immune Mechanisms and Can Result in the Destruction of the Mammalian Humoral Immune System

“…This occurred in the presence of IFNγ and IL-2, but the absence of IL-4 and IL-5. However, when repeating these measurements in IL-4 knock-out mice, a significant decrease in IgG1 titers was observed, indicating a role for this cytokine in the regulation of B cell activity, independent of antigen specific Th1 or Th2 cells (78). In the same context, IgG switching was also observed in experimental T brucei infections in both WT and nu/nu BALB/c mice, with IgG1, IgG2a, IgG2b, and IgG3 isotype antibodies being produced independent of conventional T cell help (79).…”