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The Journal of Immunology, 2003, 171: 4979-4983.
Copyright © 2003 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: {gamma}{delta} T Cells Provide Help to B Cells with Altered Clonotypes and Are Capable of Inducing Ig Gene Hypermutation1

Biao Zheng2, Ekaterina Marinova, Jin Han, Tse-Hua Tan and Shuhua Han

Department of Immunology, Baylor College of Medicine, Houston, TX 77030


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
It has not been resolved whether {gamma}{delta} T cells can collaborate with germinal center B cells and support Ig hypermutation during an Ab response to a truly defined T-dependent Ag. In this study, we show that in the absence of {alpha}{beta} T cells, immunization with the well-defined T-dependent Ag, (4-hydroxy-3-nitrophenyl) acetyl (NP) conjugate, was able to induce Ig hypermutation. However, the clonotypes of B cells responding to NP were dramatically altered in TCR {beta}-/- mice. Unlike B cells in wild-type mice that use canonical VDJ rearrangements, most NP-responding B cells in mutant mice use analog genes of the J558 gene family. In addition, the majority of anti-NP Abs produced in mutant mice use {kappa}L chain instead of {lambda}1L chain, which dominates in mice of Ighb background. Thus, the B cell population that collaborates with {gamma}{delta} T cells is distinct from B cells interacting with conventional {alpha}{beta} Th cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Affinity maturation of Ab responses occurs as a result of selecting B cell clones that have undergone Ig somatic hypermutation (SHM)3 and have acquired high affinity B cell Ag receptors (BCRs) (1, 2). It has been accepted that germinal centers (GCs) are the primary sites for Ig SHM, affinity maturation coupled with Ag-driven clonal selection, and development of B cell memory (3, 4); however, the precise mechanisms responsible for initiation/maintenance of SHM and memory development in GC are largely unknown.

Under physiological conditions, GC reaction, SHM, and B cell memory development occur during responses to T-dependent (Td) Ags, suggesting that signals from Th cells are necessary for these processes. Interactions between B and T cells depend upon activation signals delivered by BCR and TCR complexes and by costimulatory signals that modulate lymphocyte activation. During primary response, these interactions first occur when Ag-activated T and B cells meet in the T cell zone of lymphoid tissues (5). Later, selected T and B cells migrate into the follicular areas and renew their collaborations to initiate the GC reaction (6, 7). T cell population is a minor ({approx}5–15%), but requisite, component of the GC reaction (8, 9). GC T cells are unique helpers that have distinct phenotypes and functions. In mice, GC T cells are CD4+ and most of them bear {alpha}{beta} TCR specific for the eliciting Ags (4, 6, 7). It has been found that mouse GC T cells are distinct from other peripheral {alpha}{beta} TCR+CD4+ cells in that they express little or no Thy-1 (CD90) that marks most cells in the murine T cell lineage (6). Human GC T cells are also phenotypically distinct {alpha}{beta} T cells (CD4+, CD45RO+) that express CD57 and early (CD69), but not late (CD25, CD71), markers of cell activation (10).

The capability of {gamma}{delta} T cells to collaborate with B cells and activate the SHM mechanism is not clarified. To stringently test whether, in a truly defined Td response, {gamma}{delta} T cells are able to induce GC formation and Ig SHM, we analyzed the anti-(4-hydroxy-3-nitrophenyl) acetyl (NP) response in TCR {beta}-deficient mice.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Ags, mice, and immunization

Eight- to 12-wk-old C57BL/6 (H-2b) and TCR {beta}-deficient (H-2b) mice of both sexes were purchased from The Jackson Laboratory (Bar Harbor, ME). For primary responses, mice were immunized with a single i.p. injection of 50 µg of alum-precipitated NP conjugated to chicken {gamma} globulin (CGG). For secondary immunization, 20 µg of soluble NP-CGG in PBS was given i.p.

Immunohistology and flow cytometry

Sections of individual spleens were stained with peanut agglutinin (PNA) and photographed (6). The areas of PNA+ GCs were determined planometrically. GC volumes were then determined relative to the total splenic volumes of the surveyed sections (11). Biotinylated Abs to CD4, CD8, {alpha}{beta} TCR, {gamma}{delta} TCR, CD3, or CD90 were all from BD PharMingen (La Jolla, CA).

Splenocytes were stained with FITC-labeled GL-7, PE-conjugated anti-Fas, and tri-color-conjugated anti-B220 (BD PharMingen), after incubation with anti-Fc{gamma}III/IIR to block Fc{gamma}R-mediated binding. Samples were collected on a FACScan machine (BD Biosciences, Mountain View, CA) and analyzed using Flow Jo software (Tree Star, San Carlos, CA).

Microdissection of cells from tissue sections

Spleen sections were stained with PNA-HRP to visualize GCs. About 20~100 cells were picked from individual PNA+ GCs using a set of micromanipulators as previously described (5, 6).

PCR amplification and sequencing of rearranged Ig H chain genes from single splenic GCs

Cellular materials were incubated with proteinase K overnight at 37°C. The lysate was subjected to two rounds of 40 cycle PCR amplification using the Expand High Fidelity PCR kit (Boehringer Mannheim, Indianapolis, IN). According to the manufacturer, a PCR error rate of 8.5 x 10-6 per cycle is expected from the polymerase. Therefore, 80 cycles of amplification would generate one misincorporation in ~1700 bp ({approx}0.06%). We have sequenced eight VDJ clones from two independent amplifications of DNA recovered from the pEVHC{gamma}1 transfectoma (germline VH186.2-DFL16.1-JH2/{lambda}1) (12) and found no mutation. All procedures for PCR, DNA cloning, and sequencing were performed as previously described (13). All sequence data are available from European Molecular Biology Laboratory/GenBank/DNA Database of Japan under the following accession numbers: AY035667-AY035700 (VDJ sequences from wild-type mice) and AY239820-AY239892 (VDJ sequences from TCR {beta}-deficient mice).

Measurement of serum Abs

Serum Abs specific for the NP hapten were detected by ELISA using NP-BSA as the coating Ag as described (12).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
{gamma}{delta} T cells are able to support GC formation upon immunization with Td Ag

It has been accepted that the GC reaction is a T cell-dependent event (9, 10, 14, 15). However, it has been reported that immunization with type II T-independent (Ti) Ag induced GCs in TCR {beta}{delta}-/- mutant mice (16), formally demonstrating that Ti Ags are truly "T-independent" in inducing GC formation. It has also been shown that TCR {beta}-/- mice could develop GCs after repeated infection with parasites (17) which contain very complex Ag components including type I and II Ti Ags. To date, it has never been demonstrated whether {gamma}{delta} T cells can support GC formation induced by truly defined Td Ags.

To investigate whether GC reaction can be induced in a primary response to Td Ags in the absence of {alpha}{beta} T cells, we immunized TCR {beta}-deficient mice with the hapten-carrier conjugate, NP-CGG. After 12 days, spleens were harvested for immunohistologic and flow cytometric analyses (Figs. 1 and 2). As demonstrated by immunohistology, TCR {beta}-deficient mice were able to develop morphologically typical splenic GCs upon immunization (Fig. 2), although the number and sizes of GCs developed in mutant mice were significantly reduced, as compared with those of GCs in wild-type mice (Fig. 1B). Consistent with in situ staining, the percentage of PNA+Fas+ GC B cells present in splenic cells of TCR{beta}-/- and wild-type mice were 0.53 ± 0.14 (mean ± SE) and 2.99 ± 0.22, respectively (Fig. 1B). These results demonstrated that {gamma}{delta} T cells can collaborate with B cells to mount GC responses to a defined Td Ag, albeit to a lesser extent.



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  		FIGURE 1. GC formation in TCR {beta}-/- mice. Spleens were analyzed on day 12 after immunization. A, The percentages of GC B cells were assessed by staining splenocytes with PNA, anti-B220, and anti-Fas Abs. B, The volumes of GCs of wild-type ({blacksquare}) and TCR {beta}-/- ({blacksquare}) were determined by both flow cytometry and in situ staining as described in Materials and Methods. Data are representative of two similar experiments with four to six animals in each group (mean ± SE).

 


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  		FIGURE 2. Phenotype of GC T cells in TCR {beta}-/- mice. Consecutive spleen sections of a TCR {beta}-/- mouse were costained with PNA-HRP and biotinylated Abs to CD4 (A), CD8 (B), {alpha}{beta} TCR (C), {gamma}{delta} TCR (D), CD3 (E), or CD90 (F), followed by streptavidin-alkaline phosphatase. GCs were stained red and T cell markers were stained blue. Original magnification, x200.

 
To determine the phenotype of GC T cells in TCR {beta}-/- mice, spleen sections were labeled by PNA and various T cell markers. The costaining of GC and T cell markers clearly demonstrated that a significant number of T cells were present within GCs and these cells are {gamma}{delta} TCR+CD3+CD4+ (Fig. 2). No cells in the GC were found positively labeled by anti-{alpha}{beta} TCR (Fig. 2C). Few GC T cells are CD8+ (Fig. 2B). Similar to the findings in wild-type mice (6), GC T cells in mutant mice have down-regulated CD90 (Fig. 2F). Thus, {gamma}{delta}+ GC T cells in TCR {beta}-deficient mice seem to maintain other surface markers of wild-type {alpha}{beta}+ GC T cells. Immunoprecipitation and Western blotting were used to examine whether the {alpha}-chain can pair with the {delta}-chain in TCR {beta}-/- mice. We found that the {alpha}-chain was not detectable in anti-{delta} immunoprecipitates of T cells from {beta}-deficient mice (not shown), indicating that {alpha}{delta} TCRs were not present in TCR {beta}-deficient mice at a detectable level.

Ig SHM takes place in GCs of TCR {beta}-deficient mice

There are fundamental differences between GCs induced by Td and Ti Ags. First, the kinetics of GC reaction induced by Ti Ags is transient in that they usually abort 4–5 days after immunization (15, 16). Importantly, GCs induced by Ti Ags are unable to support SHM and B cell memory development. A recent report showed low level hypermutation in Ti Ag induced GCs (18); however, this low level of mutations cannot be selected and persevered due to the early GC abortion. Thus, even certain Ti Ags can initiate a transient GC reaction; clearly, T helpers are necessary for a full blooming and functional GC response. Although TCR {alpha}- or {beta}-deficient mice have been extensively studied in various models of autoimmunity and parasite infections (reviewed in Ref. 19), the question of whether {gamma}{delta} T cells can independently support Ig SHM has never been answered.

To determine whether GCs induced by {gamma}{delta} T cells can support SHM and the ensuing selection process, we isolated GC B cells by microdissection from spleen sections and sequenced the VDJ segments of the VHJ558 family (20). The results showed that VH genes recovered from day 12 GCs of TCR {beta}-/- mice contain 4.3 mutations per VH186.2 rearrangement, compared with 5.5 mutations per VH186.2 segment in wild-type mice. Eighty-five percent (28 of 33) of the VH186.2 segments derived from 11 GCs of 4 TCR {beta}-deficient mice contain mutations. All (34 of 34) VH186.2 segments from 6 GCs of 3 C57BL/6 wild-type mice were mutated. The mutation frequencies in TCR {beta} mutant and wild-type animals are 1.4 and 1.8%, respectively (Table I). Therefore, SHM occurred in TCR {beta}-/- mice at a comparable rate as in wild-type mice.


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  		Table I. Mutational characteristics in VH gene segments from GCs of TCR {beta}-/- and wild-type mice

 
Several lines of evidence suggest that the Ag-driven selection of B cell mutants occurs during the GC response in TCR {beta}-/- mice. First, similar to VDJ rearrangements from wild-type mice, ratios of replacement/silent mutations in complementarity determining regions (CDRs) were much higher than those in framework regions (FRs) of VH186.2 segments (Table I), indicating that mutations in the Ag-binding sites are selected and preserved. Second, 35 and 42% of the VH186.2 VDJ fragments recovered from wild-type and TCR {beta}-/- mice, respectively, carry a TGG->TTG (Trp-to-Leu) mutation at codon 33 in CDR1 (Table I). It is known that the TGG->TTG mutation at position 33 increases Ab affinity for the NP hapten by 10-fold (21, 22). This result indicates that, as in wild-type mice, affinity-enhancing mutations were positively selected and preserved in TCR {beta}-/- mice. In contrast, a mutation (AGG->GGG) at position 50 in the CDR2 region yields an Arg-to-Gly replacement, which dramatically reduces the strength of NP binding (23). This mutation was not seen in all VDJ segments recovered from either wild-type or TCR {beta}-/- mice, suggesting that this mutation has been negatively selected in both populations (Table I). Third, in the VH186.2 segments from TCR {beta}-/-mice, 61% of CDR3s contain the DFL16.1 segment and 51% of the VDJ segments encode a tyrosine at position 95 (Tyr95), which are important characteristics of high-affinity NP-specific B cells (12, 13, 24) (Table I). Similarly, in the H-chain segments from wild-type mice, 41 and 74% of the VH186.2 rearrangements contain the DFL16.1 segment and Tyr95 motif, respectively. Therefore, our data suggest that, similar to GCs supported by conventional {alpha}{beta} T cells, clonal selection following Ig hypermutation also takes place in GCs supported by {gamma}{delta} Th cells.

VH genes other than VH186.2 were also isolated from GCs of TCR {beta}-/- mice. These closely related analogues of the VH186.2 segments such as CH10, C1H4, V23, V102, and V165.1 belong to the VHJ558 gene family (20). Fifty-five percent (22 of 40) of the analog genes were mutated. As shown in Table I, the mutation frequency of analog genes was approximately one-third of that in VH186.2 segments, consistent with earlier work showing that analog VH genes recovered from wild-type mice contained mutations well below that of VH186.2 segments (13). No analog genes were found in sequences recovered from GCs of wild-type mice 12 days after immunization (Table I).

B cell repertoire in GCs induced by {gamma}{delta} T cells is distinct from that in GCs supported by {alpha}{beta} T cells

In mice of Ighb background, the Ab response to NP is restricted, most primary anti-NP Abs bear the {lambda}1L-chain, and the predominant H chain is encoded by the VH186.2 gene (20). Remarkably, the majority of VH genes from GCs in TCR {beta}-/- mice are analog genes, whereas all the VH genes from wild-type mice are the canonical VH186.2 genes. When the composition of clonotypes in GCs was analyzed, 36, 46, or 18% of individual splenic GCs from TCR {beta}-/- mice contained VH186.2, analog, or mixed rearrangements, respectively (Fig. 3B). Fifty-nine percent (10 of 17) of all unique clones (with distinct CDR3s) or 55% (44 of 73) of all the VH genes from mutant mice were encoded by analog genes including C1H4, V3, V102, V23, and V185.1 (Fig. 3, D and F).



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  		FIGURE 3. Clonotypic repertoire shift of GC B cells in TCR {beta}-/- mice. VH segments from individual GCs were sequenced and analyzed. Percentages of GCs containing VH186.2 gene (open segments), analog genes (gray segments), or both VH186.2 and analog genes (black segments) from wild-type (A) or mutant (B) mice are indicated around the periphery of each chart. Percentages of unique clones carrying VH186.2 (open segments) or analog (gray segments) genes are shown in charts C and D. Percentages of all VDJ sequences containing VH186.2 (open segments) or analog (gray segments) genes are shown in charts E and F. The total number of GCs, clones, or VDJ sequences analyzed in each group is indicated in the center of each chart.

 
Not only was the H chain gene repertoire shifted in TCR {beta}-/- mice, but also a large proportion of NP-specific Abs in mutant mice used the {kappa}L chain instead of the {lambda}1L chain. In wild-type spleens, {lambda}1+ Ab-forming foci could easily be detected and {kappa}+ B cells mostly resided outside the GCs (Fig. 4A). In marked contrast, few {lambda}1+ foci were found in TCR {beta}-/- mice and many {kappa}+ B cells were present in GCs (Fig. 4A). Consistently, by ELISA, we found that a significant portion of the NP-specific serum Abs produced in mutant mice bear the {kappa}L chain (Fig. 4B). When the predominance of {lambda}1-bearing Abs was expressed as the ratio of {lambda}1+/{kappa}+ Abs, the {lambda}1-bearing NP-specific Abs in mutant mice were only ~25% of that in wild-type mice (Fig. 4B). The majority of NP-specific Abs in mutants were IgM during primary response (1314 ± 193 µg/ml) or secondary response (970 ± 193 µg/ml), whereas IgG1 Abs were very low (0~50 µg/ml and 0~30 µg/ml in primary or secondary response, respectively). Thus, it seems that mutant mice are deficient in isotype switching and memory response.



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  		FIGURE 4. Use of {kappa}L chain by NP-specific Abs in TCR {beta}-/- mice. A, Adjacent splenic sections of a wild-type or mutant mouse were stained with PNA (red) for GCs and anti-{lambda}1 or {kappa}L chain Ab (blue). Original magnification, x200. B, NP-specific Abs 12 days after primary or secondary immunization were determined using biotin-conjugated anti-{lambda}1 or {kappa}L chain Ab as secondary Ab. The ratios of NP-specific Abs using {lambda}1 or {kappa}L chain produced in wild-type ({square}) or TCR {beta}-/- ({blacksquare}) mice are shown (mean ± SE). Data are representative of two similar experiments with four to six animals in each group.

 
These findings demonstrate that the cell population of NP-reactive B cells collaborating with {gamma}{delta} T cells is distinct from that of B cells interacting with conventional {alpha}{beta} T cells. It has been suggested that the activation and evolution of responding B cells with distinct clonotypic repertoires may depend mainly on the threshold affinity or avidity of the respective BCR for the immunizing Ag and on the signals from Th cells. It is reasonable to hypothesize that the combined avidity of BCR and coreceptors plays an important role in enriching MHC-peptide ligands on the B cells, which has been shown to influence the quality of T cell help (25). Additionally, it has been demonstrated that altered T cell help in aged mice or bypassing T cell help with the Ti form of NP would change Ab repertoire to NP (26, 27). Thus, our studies suggest that help signals provided by {gamma}{delta} T cells may be different from those by {alpha}{beta} T cells in recruiting responding B cells to the GCs.

Based on the data in this study, we conclude that although {gamma}{delta} T cells can induce GC formation and SHM after immunization with a Td Ag, signals elicited by {gamma}{delta} T cells are quite different from those delivered by {alpha}{beta} T cells. These differences in help signals may determine the requirements for Ag-driven B cell activation and differentiation. Our observation may have important implications in certain clinical circumstances, especially in patients suffering from an {alpha}{beta} T cell deficiency, such as AIDS.


   Footnotes
 
1 This work was supported by National Institutes of Health Grant R01 AG17149 (to B.Z.). Back

2 Address correspondence and reprint requests to Dr. Biao Zheng, Department of Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail address: bzheng{at}bcm.tmc.edu Back

3 Abbreviations used in this paper: SHM, somatic hypermutation; BCR, B cell Ag receptor; GC, germinal center; Td, T-dependent; CGG, chicken {gamma} globulin; PNA, peanut agglutinin; NP, (4-hydroxy-3-nitrophenyl)acetyl; Ti, T-independent; CDR, complementarity determining region; FR, framework region. Back

Received for publication June 16, 2003. Accepted for publication September 9, 2003.


   References
Top
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 Introduction
 Materials and Methods
 Results and Discussion
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