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The Journal of Immunology, 2006, 176: 4515-4519.
Copyright © 2006 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Memory B Cell Survival and Function in the Absence of Secreted Antibody and Immune Complexes on Follicular Dendritic Cells1

Shannon M. Anderson*, Lynn G. Hannum* and Mark J. Shlomchik2,*,{dagger}

* Section of Immunobiology and {dagger} Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Ag, in the form of immune complexes retained on follicular dendritic cells, has been implicated in the development and maintenance of B cell memory. We addressed this question using a H chain transgenic (Tg) mouse model that lacks secreted Ig (mIg), and thus does not deposit Ag-containing immune complexes. We compared the ability of the mIg strain and a control Tg strain, which secretes IgM, to develop and maintain long-lived memory cells. After immunization, there was an increase of Ag-specific B cells in both strains that was maintained for at least 20 wk. We labeled the long-lived Ag-specific cells with BrdU and found that this population was similarly maintained. In addition, both Tgs were able to maintain a functional memory response as measured by secondary germinal center reactions. Our studies indicate that localization of Ag on follicular dendritic cells is not necessary for development and maintenance of B cell memory.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Immunological memory protects hosts from recurrent infections. Memory responses are faster, larger, and qualitatively different from primary responses (1). For memory humoral responses, it is thought that resting, Ag-experienced B cells are partly responsible for the faster and bigger Ab responses following re-exposure to the Ag. The ability to mount a recall response can be maintained for decades in humans and for most of a rodent’s life (1). It is unclear what the requirements are for maintaining the ability to make such a response.

Many factors, such as Ag and cytokines, can affect the development and survival of memory lymphocytes (2, 3, 4, 5, 6). The role of Ag in maintaining memory B cells has been controversial. It was originally shown that recall responses diminished over time after cells enriched in memory B cells were transferred to naive recipients in the absence of Ag (7). Based on these and other studies, it has been proposed that Ag in the form of immune complexes (ICs)3 deposited on the surface of follicular dendritic cells (FDCs) via complement receptors and FcRs is necessary for the maintenance of memory B cells and secondary responses (7, 8). Indeed, Ag can be stored on FDCs for >1 year in mice (9). However, the role of Ag retained as ICs on FDCs in B memory maintenance has not yet been directly tested. Instead, in the studies described above, there was either the presence or absence of all immunizing Ag. Another limitation of these studies is that the measurement of memory relied on a functional readout from the donor cells, instead of a direct enumeration of the memory cells. These experiments also relied on cell transfer into irradiated recipients, which could have affected memory cell survival or responses.

The issue of Ag dependence in B cell memory was evaluated in an elegant study in which the specificity of the BCR on (4-hydroxy-3-nitrophenyl) acetyl (NP)-specific memory cells was switched after the primary response to a BCR that bound PE (10). The maintenance of this V region-switched population was measured by direct enumeration of the PE-specific B cells. These studies concluded that memory B cell maintenance was independent of the immunizing Ag, regardless of where or in what form it was. Although these results were clear, this manipulation of specificity from the B cell perspective has only been applied to a single system. In view of ongoing conflicting data from other systems (8), consensus still has not been reached, and the positive roles of Ag trapped on FDCs have never been directly addressed. Moreover, the experimental design required waiting until memory was already established before switching the specificity. Thus, it was only able to address whether Ag was necessary for maintenance of established memory and did not distinguish whether Ag was required during the period between the active germinal center (GC) response and the completion of memory development. In addition, in prior work, the ability of maintained, V region-switched cells to make a secondary response was not tested in vivo (10).

In this study, we have directly addressed whether Ag deposited on FDCs is necessary for the development and maintenance of memory B cells by making mice (mIg; Ref.11) that lacked secreted Ab and therefore lacked Ag-containing ICs. We have previously shown that mIg mice do not have detectable Ag deposition on FDCs, and make normal GC responses with equivalent size, levels of activation, and patterns of selection as a control strain, the (m+s)Ig mice, which do secrete IgM and exhibit Ag deposition on FDCs (11). These two types of mice, which have the same BCR and only differ in Ig secretion, allowed us to test first whether ICs were necessary for the development and maintenance of memory B cells. We show in this study that by manipulating Ag deposition rather than B cell specificity, there is indeed memory B cell development and maintenance in the absence of Ag-containing ICs, and that it is quantitatively and qualitatively similar to that observed in the control strain.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Mice and immunizations

Mice and NP Ags used have been described previously (11). The strain in this study called mIg is formally designated as follows: C.Cg-Igh-J<tm1Dhu> Tg(Igh-VB1-8/Igh-6m)1Mjsk; and the (m+s) strain is designated as follows: C.Cg-Igh-J<tm1Dhu> Tg(Igh-VB1-8/Igh-6)2Mjsk. For primary responses, mice were immunized i.p. with 50 µg of NP25-chicken-{gamma}-globulin (NP25-CGG) precipitated in alum or precipitated alum alone as a control. For secondary responses, mice were given 50 µg of NP17-human serum albumin (HSA) i.v. in PBS 12 wk after the first immunization.

Flow cytometry

Staining of cell suspensions and production of (4-hydroxy-5-iodo-3-nitrophenyl) acetyl (NIP)-binding reagents was as described previously (11). Live/dead discrimination was done using ethidium monoazide (Molecular Probes). Anti-B220 (RA3-6B2) was conjugated to AlexaFluor 647 (Molecular Probes). Samples were analyzed on a BD FACSCalibur (BD Biosciences) and analyzed with FlowJo software (Tree Star).

BrdU detection

For BrdU labeling, mice were given i.p. injections of 0.6 mg of BrdU (Sigma-Aldrich) every 12 h from 11 to 14 days postimmunization. For the determination of naive B cell half-lives, BrdU was given to naive mice for up to 7 days. Detection of BrdU in cells was essentially as described previously (12).

Histology and quantitation of GC area

Freezing, sectioning, and staining of spleen sections were performed as described previously (11). Sections were stained with peanut agglutinin (PNA)-biotin (Vector Laboratories), using streptavidin-HRP (Molecular Probes) as the secondary reagent, and goat anti-{lambda}-alkaline phosphatase (Southern Biotechnology Associates). The number of PNA+{lambda}+ GCs was determined by counting from random x40 views of each group. The relative area (in pixel number) of each GC from a x40 view was measured using Image-Pro Plus-3 software (Media Cybernetics).

Statistics

Unpaired, two-tailed t tests were performed with Microsoft Excel. p values of <0.05 were considered significant.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
The Vh186.2 chain used in both transgenic (Tg) lines generates an NP-specific BCR in combination with the {lambda}1 L chain, and the response to NP in these strains is almost exclusively of {lambda} type (11). To determine whether memory B cells could be generated and maintained in mice that do not deposit Ag in the form of ICs on FDCs, we immunized mIg mice or (m+s)Ig Tg mice with NP-CGG. We then measured the percentage of Ag-specific B cells in the spleen at subsequent times, using NIP binding to detect cells that bore the Ag-specific BCR. In the mIg strain, we identified a population of B220+/NIP+ cells that was increased by 2-fold in frequency (Fig. 1A) and in number (data not shown) as compared with the alum-immunized controls at 12 wk postimmunization. A similar increase was seen in the (m+s)Ig strain, although to a slightly lesser extent (a 1.5-fold difference in frequency and number). In both strains, regardless of the ability to deposit ICs, the increased frequency (Fig. 1B) and number (data not shown) of Ag-specific B cells was stable over time up to at least 20 wk postimmunization. Although the goal of these studies was not to compare the absolute responses in the two strains, we noted a greater expansion of NIP+ B cells in the mIg strain as compared with the (m+s)Ig strain, which could be due to the larger GC response in mIg mice compared with (m+s)Ig mice (11) leaving more cells to differentiate into memory cells (1). The important conclusion from these data is that once memory was established, it was similarly maintained in the two strains.


Figure 1
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  		FIGURE 1. Stable elevation in frequency of NIP+/B220+ cells in immunized mIg and (m+s)Ig mice with similar kinetics from 8 to 20 wk postimmunization. A, FACS plots of alum- and NP-CGG-immunized spleen cells stained with anti-B220-Alexa647 and NIP-PE 12 wk postimmunization. B, Frequency of Ag-specific B cells present in mIg (top) and (m+s)Ig (bottom) mice 8–20 wk postimmunization. Symbols are means (n = 7–11 mice per strain), and error bars represent SEM from at least three independent experiments for each time point. All differences between immunized and alum points were significant; p < 0.05.

 
Due to the continuous production of Ag-specific B cells in our Tg animals, there was always a significant population of naive B220+/NIP+ cells present in alum-treated and immune animals. We inferred that the difference in the percentages of NIP+ B cells in immune and alum-immunized mice must represent the fraction of NIP+ cells that were memory cells. However, because of the residual naive population, we could not conclusively identify which of the Ag-binding cells in the mixed population were memory cells. To unambiguously label memory cells, we injected BrdU i.p. for 4 days during the peak of the GC response (days 11 to 14; Ref.11), which marked B cells that had been actively dividing (Fig. 2A). We would expect this strategy to durably label those cells that derived from dividing precursors and then stopped cycling during or immediately after the labeling period. Such cells meet a stringent definition for memory cells (13, 14). Because memory cells are likely generated from GC cells throughout the multiple weeks of the reaction (S. Anderson, unpublished observation, and Ref.15), the cells labeled using this protocol would only represent a small fraction of the total memory B cell population. Nonetheless, we could use the labeled cells to trace the fate, including survival and subsequent cell division, of Ag-specific memory cells. Spleens from mice immunized 12 wk before contained a small but significant population of NIP+/BrdU+ cells (Fig. 2B). NIP+/BrdU+ cells were detected at higher frequency (Fig. 2C) and numbers (data not shown) in immune animals compared with alum-injected animals in both strains. There was an initial drop in the frequency and number of BrdU-labeled Ag-specific cells in both strains between 8 and 12 wk postimmunization, which most likely reflects the waning of the primary response. However, in both strains, from 12 wk onward the increased frequency and number of NIP+/BrdU+ cells in immune animals as compared with alum-immunized controls remained stable over time (Fig. 2C and data not shown). Along with the data on total cell frequencies and numbers of Ag-specific B cells, the BrdU-labeling data indicates that retained Ag on FDCs is not necessary for the maintenance of a long-lived memory B cell population. We did detect a drop in the frequency of NIP+/BrdU+ cells in the mIg mice at 20 wk, which was not as evident in the (m+s)Ig Tg mice, though there was no statistical difference between the BrdU label frequency curves of two strains. This may indicate dilution of BrdU to a greater extent in the mIg strain due to homeostatic proliferation of memory cells (2); it does not indicate loss of the memory compartment, because there was no drop in total NIP+ cell frequencies (Fig. 1B) or numbers (data not shown).


Figure 2
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  		FIGURE 2. Stable elevation in frequency of NIP+/B220+/BrdU+ cells labeled during the peak of the GC response in immunized Tg mice with similar kinetics in the two strains. A, Schematic representation of the experimental design. BrdU was administered i.p. every 12 h during the days indicated. B, Representative FACS plots of alum- and NP-immunized spleen cells12 wk postimmunization triple-stained with B220-Alexa647, NIP-PE, and anti-BrdU-FITC. Top row, B220 vs NIP PE; bottom row, B220 vs BrdU. C, Frequency of NIP+/BrdU+ cells in mIg (left) and (m+s)Ig (right) mice between 8 and 20 wk postimmunization. Symbols, error bars, and n’s are as in Fig. 1. All differences between immunized and alum points were significant; p < 0.0001.

 
The fact that frequencies of BrdU-labeled cells remained stable >10 wk following initial labeling demonstrated that BrdU+ Ag-specific B cells were long-lived and had a very slow rate of division. Indeed, from the 12-wk time point on, the half-life of the labeled cells in the immune animals was >8 wk (Fig. 2C). One marker of memory differentiation is an increased cell half-life compared with the half-lives of naive precursors (14). To determine the half-life of the naive B cell pool in these Tg mice, we treated unimmunized mice from both strains with BrdU continuously and measured the fraction of NIP+/BrdU+ cells in the spleen after 3, 5, and 7 days of labeling. Because the number of mature B cells in the spleen is stable in mIg and (m+s)Ig mice (our unpublished observations), the kinetics of labeling-up of the naive B cell population reflect the half-life of the cells in that compartment (12, 16). We observed labeling-up kinetics that fit well with expected exponential models, and from this calculated half-lives of the naive compartments in the mIg and (m+s)Ig mice as 24 and 18 days, respectively. Thus, the half-lives of the naive precursors were substantially shorter than their memory progeny.

The presence of long-lived B cells demonstrated that memory B cells could survive without retained Ag in the form of ICs on FDCs. We next asked whether ICs on FDCs was necessary to maintain functional memory. Although secondary responses are often measured by Ab-forming cell assays or Ab secretion, this was not possible because our system design required lack of Ab secretion in order for us to test the role of Ab itself. Secondary responses are also well documented to include accelerated and larger GC responses (17, 18). Therefore, to test whether long-lived Ag-specific B cells persisting in the mIg strain were able to mount a recall response, we measured the secondary GC reaction, because these mice were not able to produce circulating Ab. We chose to reimmunize in situ to avoid the complications that are inherent in transfer experiments that require rehoming in irradiated hosts with potentially compromised architecture. Twelve weeks postimmunization with NP-HSA in alum, mice were challenged with the Ag i.v. in PBS to elicit a memory response ("Secondary" group). To control for the considerable anticipated effects of memory T cells present in the immunized mice (17), we created a group of animals that had been immunized with the protein carrier only ("T-primed" group), which were also reimmunized with NP-HSA. Ag-specific GCs were detected in splenic sections from the Secondary group in both strains 4 days after secondary immunization (Fig. 3). Because this immunization protocol does not produce any GCs in naive mIg or (m+s)Ig mice at any of the time points examined (data not shown), this clearly represents a recall response. GCs containing {lambda}+ cells were also detected in the T-primed group in the mIg but not (m+s)Ig mice at this time point. However, these T-primed GCs were a mixture of {lambda}+ and {lambda}– (presumably {kappa}+) cells, suggesting a more predominant response to the carrier protein. Mixed GCs were also observed in the Secondary (m+s)Ig mice at day 4 but were much more homogeneously {lambda}+ at later time points (data not shown).


Figure 3
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  		FIGURE 3. GC responses following recall immunizations. Splenic sections were stained for PNA (red) and anti-{lambda} (blue) to identify Ag-specific GCs 4 days after an i.v. immunization with NP-HSA. Mice had been immunized 12 wk beforehand with either NP-HSA (Secondary, top) or HSA (T-primed, bottom). mIg (left) and (m+s)Ig (right) mice are shown. Original magnification, x200.

 
To determine whether the GC response in the Secondary group was faster and bigger than the T-primed group, we measured the extent of the GC response in these animals 4, 7, and 9 days postimmunization (Fig. 4). Because the T-primed GCs contain a mixture of {lambda} and {kappa} cells, these measurements are a maximal estimate of the NP-specific, {lambda}+ response; it was not technically feasible to measure just the {lambda}+ component. A large number of GCs (per random x40 field) were already present in spleens of Secondary mIg mice by day 4 of the response, and this number remained constant throughout the time course (Fig. 4A). In contrast, the number of GCs in the T-primed group was 2-fold lower at day 4, transiently increased at day 7 but by day 9 was ~3-fold lower than the Secondary group (Fig. 4A, left). Similar observations were made with (m+s)Ig mice, although the details of the kinetics were somewhat different. The secondary response appears to peak slightly later in the (m+s)Ig mice than in mIg mice. Most importantly, in (m+s)Ig mice, at every time point, there were also substantially fewer GCs in the T-primed group compared with the Secondary group (Fig. 4A, right). In addition to the greater numbers of GCs in the Secondary group as compared with the T-primed group, the sizes of the GCs themselves were also larger in the Secondary groups of both strains (Fig. 4B). The product of the average number of GCs per x40 view and the average area per GC (Fig. 4C) reflects the total GC volume. This analysis shows even more clearly that the responses in the Secondary groups were significantly greater at all time points than the responses in the T-primed groups in either strain. The enhanced response of the T-primed groups compared with naive mice was expected, because it is known that the presence of primed T cells promotes a quick expansion of GCs followed by an equally quick resolution (17). Nonetheless, when memory B cells are present, the GC response is more robust and sustainable (Fig. 4A). Thus, functional memory as determined by secondary GC responses correlates with memory cells as enumerated by FACS, and neither measure appears dependent on the presence of ICs on FDCs. Because we could not measure Ab responses, we cannot exclude that functional secondary Ab responses might have been affected differently, although no effect was seen on overall memory cell number.


Figure 4
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  		FIGURE 4. GCs appear more quickly and are larger in Secondary compared with T-primed immunization in mIg and (m+s)Ig mice. At the indicated days post secondary immunization, mIg (left) or (m+s)Ig (right) mice were sacrificed, and their spleens were stained with PNA and anti-{lambda}. A, Average number of GCs per x40 view. Error bars represent SEM, n = 25–50 GCs for mIg, and n = 1–6 for (m+s)Ig mice. Lower numbers of GCs were counted when GCs were only rarely seen as at day 4. B, The average area per GC was measured in pixel number from x40 views. Error bars represent SEM, n = 7–14 GCs for mIg, and n = 0–12 for (m+s)Ig mice. C, Plotted is the product of the means from graphs in A and B for each group. Error bars represent the propagated error from each multiplicand. *, p < 0.05; **, p < 0.01; ***, p < 0.001.

 
We have presented data demonstrating that Ag in the form of ICs is not necessary to maintain a memory B cell population. We want to point out clearly that we do not exclude the possibility that Ag could exist in mice in another form; however, most models of Ag retention have invoked Ag-Ab complexes on FDC as the likely site, because this is where intact Ag is most evident (19). These conclusions complement those of Maruyama et al. (10), who found by switching the BCR of an established memory population that signals through the BCR from Ag were not necessary to maintain a late memory population. Whereas their studies rendered the B cell insensitive to all immunizing Ag, our experiments evaluated whether Ag in the form of ICs on FDCs was necessary. Importantly, we have additionally shown that Ag in the form of ICs on FDCs is not required for memory development immediately following the GC reaction, an important interval that was not evaluated previously (10).

In Maruyama et al. (10), in unimmunized mice, there was an equal percentage of PE+IgM+ B cells as NP+IgM+ B cells (3.0 vs 2.6%) following induction of Cre-mediated receptor switching. However, in mice 8–10 wk postimmunization, it was notable that following the induction of receptor switching, there was an ~10-fold difference between the PE+ and NP+ populations (~5 vs ~43%; Ref.10). Although, as suggested by the authors, some of this difference could be accounted for by unselected hypermutation that would render the V region-encoding PE nonfunctional, not all of the 10-fold difference could be accounted for this way because only ~60% of V region sequences had mutations. Thus, it was possible in these studies that some B cells were in fact lost due to switching of specificity. In view of our data, it now seems more likely that switching the receptor at 8 wk affected some of the ongoing GC response, rather than the memory compartment, perhaps leading to fewer cells being recruited into the memory pool (10).

In contrast to our findings, classical and recent studies have suggested a requirement for Ag in the maintenance of memory (7, 8). The conflicting conclusions could be explained by the use of different assays for memory. We enumerated memory cells directly. In the other studies, the measurement of memory was indirect, depending on a functional response from transferred cells of immune mice. This readout reflects not only the survival of the memory cells, but also their ability to differentiate. In some cases, it was also difficult to distinguish the donor from the host response, because host B cells reconstituted sublethally irradiated recipients (8). Studies that indicated a role for Ag in memory maintenance used cell transfer, whereas those that did not measured memory in intact animals. With cell transfer, the environment that the memory cells inhabited was disrupted, and the ability of the donor memory cells to survive could have been altered. In these circumstances, reimmunization early after transfer (i.e., "adding Ag") could have rescued memory cells.

In this study, we have focused on the central issues of development and survival of memory B cells, finding that ICs on FDCs are not required for either to occur. A limitation of our study is the inability to measure functional Ab secretion (a necessary consequence of the experimental design), although we do show that long-lived Ag-specific memory B cells promote an accelerated and larger GC reaction. They also have different phenotypic and gene expression profiles (S.M. Anderson, M.M. Tomayko, and M.J. Shlomchik, manuscript in preparation). A second limitation is that we only look at IgM memory cells, which are known to exist in mice and are abundant in humans (20). Although we expect that the dependence of IgG memory cells on FDC-associated ICs should be similar to IgM memory cells, we cannot directly show that with this system. Nonetheless, the ability to label B cells that have responded during the GC reaction and track them at a much later time has permitted us to survey the properties of memory cells. One of these properties is the presence of mutations in the rearranged V regions of Ig genes (15, 20, 21). Indeed, V regions of long-lived, Ag-specific B cells from immunized mIg and (m+s)Ig mice do contain mutations; the scope and analysis of this sequence dataset is complex and will be presented elsewhere. This system should thus prove useful in determining other properties of naive and memory cells that make secondary responses quantitatively and qualitatively different.


   Acknowledgments
 
We thank David Schatz, Ann Haberman, Mary Tomayko, and Al Bothwell for critical reading of the manuscript and Klaus Rajewsky for discussions. We thank Michelle Horniak, Terrence Hunt, and the staff of the Yale Animal Resources Center for outstanding animal care.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by National Institutes of Health Grant AI43603. S.M.A. was the recipient of a Trudeau Fellowship from Yale University. Back

2 Address correspondence and reprint requests to Dr. Mark J. Shlomchik, Department of Laboratory Medicine, Yale University School of Medicine, Box 208035, New Haven, CT 06520-8035. E-mail address: mark.shlomchik{at}yale.edu Back

3 Abbreviations used in this paper: IC, immune complex; FDC, follicular dendritic cell; NP, (4-hydroxy-3-nitrophenyl) acetyl; GC, germinal center; NP-CGG, (4-hydroxy-3-nitrophenyl) acetyl chicken-{gamma}-globulin; HSA, human serum albumin; NIP, (4-hydroxy-5-iodo-3-nitrophenyl) acetyl; PNA, peanut agglutinin; Tg, transgenic. Back

Received for publication January 13, 2006. Accepted for publication February 17, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

  1. Ahmed, R., D. Gray. 1996. Immunological memory and protective immunity: understanding their relation. Science 272: 54-60. [Abstract]
  2. Murali-Krishna, K., L. L. Lau, S. Sambhara, F. Lemonnier, J. Altman, R. Ahmed. 1999. Persistence of memory CD8 T cells in MHC class I-deficient mice [see comments]. Science 286: 1377-1381. [Abstract/Free Full Text]
  3. Swain, S. L., H. Hu, G. Huston. 1999. Class II-independent generation of CD4 memory T cells from effectors. Science 286: 1381-1383. [Abstract/Free Full Text]
  4. Gray, D., P. Matzinger. 1991. T cell memory is short-lived in the absence of antigen. J. Exp. Med. 174: 969-974. [Abstract/Free Full Text]
  5. Ku, C. C., M. Murakami, A. Sakamoto, J. Kappler, P. Marrack. 2000. Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 288: 675-678. [Abstract/Free Full Text]
  6. Tan, J. T., B. Ernst, W. C. Kieper, E. LeRoy, J. Sprent, C. D. Surh. 2002. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J. Exp. Med. 195: 1523-1532. [Abstract/Free Full Text]
  7. Gray, D., H. Skarvall. 1988. B-cell memory is short-lived in the absence of antigen. Nature 336: 70-73. [Medline]
  8. Barrington, R. A., O. Pozdnyakova, M. R. Zafari, C. D. Benjamin, M. C. Carroll. 2002. B lymphocyte memory: role of stromal cell complement and Fc{gamma}RIIB receptors. J. Exp. Med. 196: 1189-1199. [Abstract/Free Full Text]
  9. Tew, J., T. E. Mandel, A. W. Burgess. 1979. Retenetion of intact HSA for prolonged periods in the popliteal lymph nodes of specifically immunized mice. Cell. Immunol. 45: 207-212. [Medline]
  10. Maruyama, M., K. P. Lam, K. Rajewsky. 2000. Memory B-cell persistence is independent of persisting immunizing antigen. Nature 407: 636-642. [Medline]
  11. Hannum, L. G., A. M. Haberman, S. M. Anderson, M. J. Shlomchik. 2000. Germinal center initiation, variable gene region hypermutation, and mutant B cell selection without detectable immune complexes on follicular dendritic cells. J. Exp. Med. 192: 931-942. [Abstract/Free Full Text]
  12. Allman, D. M., S. E. Ferguson, V. M. Lentz, M. P. Cancro. 1993. Peripheral B cell maturation. II. Heat-stable antigenhi splenic B cells are an immature developmental intermediate in the production of long-lived marrow-derived B cells. J. Immunol. 151: 4431-4444. [Abstract]
  13. Coico, R. F., B. S. Bhogal, G. J. Thorbecke. 1983. Relationship of germinal centers in lymphoid tissue to immunolgic memory. IV. Transfer of B cell memory with lymph node cells fractionated according to their receptors for peanut agglutinin. J. Immunol. 131: 2254-2257. [Abstract]
  14. Schittek, B., K. Rajewsky. 1990. Maintenance of B-cell memory by long-lived cells generated from proliferating precursors. Nature 346: 749-751. [Medline]
  15. Takahashi, Y., H. Ohta, T. Takemori. 2001. Fas is required for clonal selection in germinal centers and the subsequent establishment of the memory B cell repertoire. Immunity 14: 181-192. [Medline]
  16. Forster, I., K. Rajewsky. 1990. The bulk of the peripheral B-cell pool in mice is stable and not rapidly renewed from the bone marrow. Proc. Natl. Acad. Sci. USA 87: 4781-4784. [Abstract/Free Full Text]
  17. Liu, Y. J., J. Zhang, P. J. Lane, E. Y. Chan, I. C. MacLennan. 1991. Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens. Eur. J. Immunol. 21: 2951-2962. [Medline]
  18. Vora, K. A., K. Tumas-Brundage, T. Manser. 1999. Contrasting the in situ behavior of a memory B cell clone during primary and secondary immune responses. J. Immunol. 163: 4315-4327. [Abstract/Free Full Text]
  19. Gray, D.. 2002. A role for antigen in the maintenance of immunological memory. Nat. Rev. Immunol. 2: 60-65. [Medline]
  20. Klein, U., K. Rajewsky, R. Kuppers. 1998. Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J. Exp. Med. 188: 1679-1689. [Abstract/Free Full Text]
  21. Cumano, A., K. Rajewsky. 1986. Clonal recruitment and somatic mutation in the generation of immunological memory to the hapten NP. EMBO J. 5: 2459-2468. [Medline]



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S. M. Anderson, M. M. Tomayko, A. Ahuja, A. M. Haberman, and M. J. Shlomchik
New markers for murine memory B cells that define mutated and unmutated subsets
J. Exp. Med., September 3, 2007; 204(9): 2103 - 2114.
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K. Kumazaki, B. Tirosh, R. Maehr, M. Boes, T. Honjo, and H. L. Ploegh
AID-/-{micro}s-/- Mice Are Agammaglobulinemic and Fail to Maintain B220-CD138+ Plasma Cells
J. Immunol., February 15, 2007; 178(4): 2192 - 2203.
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Z. S. M. Rahman, B. Alabyev, and T. Manser
Fc{gamma}RIIB Regulates Autoreactive Primary Antibody-Forming Cell, but Not Germinal Center B Cell, Activity
J. Immunol., January 15, 2007; 178(2): 897 - 907.
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