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. 2002 May 6;195(9):1215-21.
doi: 10.1084/jem.20011550.

Very low affinity B cells form germinal centers, become memory B cells, and participate in secondary immune responses when higher affinity competition is reduced

Joseph M Dal Porto  1 , Ann M Haberman, Garnett Kelsoe, Mark J Shlomchik
Affiliations

Very low affinity B cells form germinal centers, become memory B cells, and participate in secondary immune responses when higher affinity competition is reduced

Joseph M Dal Porto et al. J Exp Med. .

Abstract

To understand the relationship between the affinity of the B cell antigen receptor (BCR) and the immune response to antigen, two lines of immunoglobulin H chain transgenic (Tg) mice were created. H50Gmu(a) and T1(V23)mu(a) mice express mu H chain transgenes that associate with the lambda1 L chains to bind the (4-hydroxy-3-nitrophenyl)acetyl hapten with association constants (K(a)s) of only 1.2 x 10(5) M(-1) and 3 x 10(4) M(-1), respectively. Both lines mounted substantial antibody-forming cell (AFC) and germinal center (GC) responses. H50Gmu(a) Tg mice also generated memory B cells. T1(V23)mu(a) B cells formed AFC and GCs, but were largely replaced in late GCs by antigen-specific cells that express endogenous BCRs. Thus, B lymphocytes carrying BCRs with affinities previously thought to be irrelevant in specific immune responses are in fact capable of complete T cell-dependent immune responses when relieved of substantial competition from other B cells. The failure to observe such B cells normally in late primary responses and in memory B cell populations is the result of competition, rather than an intrinsic inability of low affinity B cells.

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Figures

Figure 1.
Figure 1.
Humoral immune response in low affinity H50Gμa and T1(V23)μa Tg mice. (A) H50Gμa (○) and C.B-17 controls (•) were injected intraperitoneally with NP-CG in alum. Serial dilutions of sera were assayed for NP binding of total Ig, Tg IgMa, anti-NP characteristic λ1, and IgG1. *, H50Gμa mice in which significant anti-NP IgG1 titers may have affected the measurement of IgMa Tg levels. (B) Sera from H50Gμa and control C.B-17 mice after immunization with NP-CG were assayed for their ability to bind NP-BSA after 2-ME treatment (shaded bars) or mock treatment (solid bars). The change in the relative NP binding of treated samples is shown as a percentage change from mock-treated samples. Values represent the mean values (± SD) obtained from three independent experiments. T1(V23)μa Tg mice (▴) were compared with H50Gμa (○) and C.B-17 (•) mice in response to (C) NP-CG or (D) NIP-CG in alum. Sera were assayed for NP-binding components. Each symbol represents the average endpoint dilution value of serum from an individual mouse measured in triplicate.
Figure 2.
Figure 2.
GC formation in H50Gμa mice 12 d after immunization with NP-CG. Splenic serial sections reveal PNA+ GC B cells (red) that were labeled in tandem (blue) for: (A) Tg IgMa+; (B) endogenous IgMb+; (C) λ1 L chain; and (D) κ L chain. rp, red pulp; pals, periarteriolar lymphoid sheath; gc, germinal center. Note that surface Ig staining is weak in GCs due to marked surface IgM down-regulation in GCs. However, the difference between the (A) IgMa and (B) IgMb staining of the same GC can be appreciated by how the IgMa staining modifies the color of the PNA-stained GC cells. A similar picture is seen comparing (C) λ1 and (D) κ staining. ×100.
Figure 3.
Figure 3.
GCs in H50Gμa mice have increased frequencies of endogenous BCRs and enhanced apoptosis. PNA+ GCs (red) from H50Gμa mice (A) 12, (B) 16, (C) and 20 d after immunization with NP-CG were stained for the presence of endogenous Ig (blue, IgMb or IgG1). For detecting apoptotic GC cells, (D) H50Gμa and (E) C.B-17 sections of spleen from mice at day 16 of the primary immune response were labeled by TUNEL+ (red) and with anti-IgM (blue). GCs appear as faint blue areas within darker blue follicles due to surface Ig downmodulation on GC B cells.
Figure 4.
Figure 4.
Affinity maturation of the humoral response in H50Gμa mice. Bars show the NP5/NP22 binding ratio for IgMa Ab. Endpoint titers for NP5- (▵) and NP22- (○) binding IgMa from H50Gμa mice are superimposed to demonstrate the actual Ab concentration shifts during the response. The response of naive H50Gμa mice to a primary intravenous immunization with soluble NP-CG is also shown (▿). Values represent the mean ± SD (error bars) of four or five mice for each time point.
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