CD81 on B cells promotes interleukin 4 secretion and antibody production during T helper type 2 immune responses - PubMed (original) (raw)

CD81 on B cells promotes interleukin 4 secretion and antibody production during T helper type 2 immune responses

H T Maecker et al. Proc Natl Acad Sci U S A. 1998.

Abstract

Mice lacking CD81 (TAPA-1), a widely expressed tetraspanin molecule, have impaired antibody responses to protein antigens. This defect is specific to antigens that preferentially stimulate a T helper 2 response (ovalbumin or keyhole limpet hemocyanin in alum) and is only seen with T cell-dependent antigens. Absence of CD81 on B cells is sufficient to cause the defect. Also, antigen-specific interleukin (IL) 4 production is greatly reduced in the spleen and lymph nodes of CD81-null mice compared with heterozygous littermates. Thus, expression of CD81 on B cells is critical for inducing optimal IL-4 and antibody production during T helper 2 responses. These findings suggest that CD81 may interact with a ligand on T cells to signal IL-4 production. By using a soluble form of CD81 as a probe, a putative ligand for CD81 was identified on a subset of B and T cells. Two possible models for the interaction of CD81 on B cells with a potential ligand on either B or T cells are proposed.

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Figures

Figure 1

Figure 1

(A–C) Response of CD81-null mice to T dependent antigens varies with adjuvant. CD81-null mice (solid bars) and heterozygous littermates (hatched bars) were immunized i.p. with ovalbumin or KLH either precipitated in alum or given with QS-21 or IL-12 as adjuvants. Antigen-specific serum antibody responses were measured 12 weeks after a single immunization (primary) or 18 days after a second injection (boost). (A) Responses of CD81-null mice were significantly lower than heterozygotes to ovalbumin or KLH in alum, which induces a Th2 response. (B) Responses of CD81-null mice were not significantly different from heterozygotes when immunized with ovalbumin in QS-21 or KLH in IL-12, which stimulate a Th1 response. (C) The IgG1 response to ovalbumin in alum was significantly decreased in CD81-null mice. IgG2a responses to ovalbumin in alum were not significantly different between groups. (D) Response of CD81-null mice to a T independent antigen. CD81-null mice (▪) and heterozygous littermates (□) were immunized i.p. with 25 μg of TNP-Ficoll. The serum antibody response to TNP was measured by ELISA at 7 and 14 days. There were no significant differences between groups. Data are the means ± SEM (n = 3 to 9 animals per group).

Figure 2

Figure 2

Chimeric mice were constructed by injection of CD81−/− ES cells (solid bars) or CD81+/+ ES cells (hatched bars) into blastocysts from B cell-deficient mice. (A) Total serum Ig of chimeric mice at 12 weeks of age. (B) Response of chimeric mice to ovalbumin in alum. Chimeric mice were immunized with ovalbumin in alum, and serum anti-ovalbumin antibody was measured at 4, 8, and 12 weeks after a single injection. Mice were then given a booster injection and secondary responses were measured 18 days later. Error bars indicate the SEM (n = 2 to 10 animals per group).

Figure 3

Figure 3

Antigen-specific IL-4 and IFN-γ responses in CD81-null mice (solid bars) and heterozygous littermates (hatched bars). Mice were immunized three times with the specified antigen in alum. Spleens and peripheral lymph nodes were removed 4 days after the last injection. Mononuclear cells were restimulated with ovalbumin or KLH for 3 days, then supernatants were harvested, and cytokines measured by ELISA (25). Bars indicate the SD of triplicate cultures.

Figure 4

Figure 4

Schematic models for the role of CD81 in Th2 responses. In the simplest model (A), CD81 on B cells interacts directly with a putative ligand on T cells, stimulating IL-4 production, which leads to IgG1 antibody production. The interacting T cells expressing CD81 ligand may be those already committed to Th2 development, or they may be recruited into this pathway upon interaction with B cells expressing CD81. In a slightly different model (B), B cells interact first with a subset of other B cells expressing the putative CD81 ligand. These B cells then interact with T cells via cell contact and/or soluble factors to induce IL-4 secretion and IgG1 antibody production.

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