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The Journal of Immunology, 1998, 161: 4472-4475.
Copyright © 1998 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Senescent BALB/c Mice Exhibit Decreased Expression of {lambda}5 Surrogate Light Chains and Reduced Development Within the Pre-B Cell Compartment1

Erin M. Sherwood, Bonnie B. Blomberg, Wei Xu, Cynthia A. Warner and Richard L. Riley2

* Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33101


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Although senescent BALB/c mice (~2 years old) have reduced numbers of small pre-B cells, early pre-B cells (CD43+CD25+B220+) are present in comparable numbers within the bone marrow of both young (3–6-month-old) and senescent BALB/c mice. The transition of CD43+ pre-B cells to the CD43- pre-B cell compartments is dependent on proliferation and clonal maturation dictated by the pre-B cell receptor (µ/{lambda}5/VpreB). In vivo, senescent CD43+B220+ pro-B/early pre-B cells demonstrated reduction of {lambda}5 mRNA, by RT-PCR analysis, and of both surface and cytoplasmic {lambda}5 protein. Decreased {lambda}5 protein expression was also seen among pro-B/pre-B cells derived from senescent bone marrow after stimulation in vitro with IL-7. We propose that diminished expression of the {lambda}5 surrogate light chain results in decreased pre-B cell receptor formation and contributes to reduced recruitment of nascent CD43+ pre-B cells into the CD43- large and small pre-B cell compartments.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Senescent mice typically exhibit decreased numbers of pre-B cells in their bone marrow, suggesting that abnormal B lymphopoiesis accompanies the aging process (1, 2, 3). Although pre-B cell numbers are reduced in senescent murine bone marrow, it has been reported that the numbers of pro-B cells remain unchanged (2, 3), indicating that the abnormal development of pre-B cells in aged mice occurs at the pro-B cell to pre-B cell transition. Stephan et al. (4) have also suggested that decreased proliferation in response to the growth cytokine IL-7 may contribute to diminished pre-B cell production by limiting expansion of nascent pre-B cells.

Expression of the pre-B cell receptor (µ/{lambda}5/VpreB) is required for optimal clonal expansion and maturation of pre-B cells (5, 6, 7). Although critical to the establishment of normal steady state numbers of pre-B cells, there currently is no information regarding expression and/or function of the pre-B cell receptor during senescence. In this report, we demonstrate that early CD43+ pre-B cells are retained in senescent BALB/c mice while later CD43- pre-B cells are decreased. Importantly, the expression of {lambda}5 surrogate light chain mRNA and protein within the pro-B/early pre-B cell population is significantly reduced in aged BALB/c mice. We suggest that decreased {lambda}5 surrogate light chain expression contributes to the decline in B lymphopoiesis observed in senescence.


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

Young male and female BALB/c mice 3 to 6 mo of age and senescent BALB/c mice 22 to 29 mo of age were obtained from the National Institute on Aging colony at Charles River Laboratories, Wilmington, MA. Mice bearing visible tumors were eliminated from the study. Comparable results were seen with both males and females.

Fluorescent staining and cell sorting

Bone marrow cells were stained with mAbs specific for CD43 (clone S7), B220 (clone RA3-6B2), CD19 (clone D7), and/or CD25 (clone 7D4) (PharMingen, San Diego, CA) by methods previously reported (2). The LM34 mAb, specific for murine {lambda}5, was produced by Karasuyama et al. (8) and generously provided by Dr. Hans-Martin Jäck, Department Medicine, University of Erlangen-Nurnberg, Erlangen, Germany, with permission of Dr. Fritz Melchers, Basel Institute of Immunology, Basel, Switzerland. LM34 was biotin labeled with a sulfo-NHS-biotinylation kit (Pierce, Rockford, IL). Panning to remove B cells in some experiments was performed as reported (2). Bone marrow CD43+B220+ and both large and small CD43-B220+ or CD25+B220+ cells were separated on a FACStarPlus cell sorter (Becton Dickinson). Purity of the sorted populations was >95% according to reanalysis for surface stains.

In vitro expansion of IL-7-dependent pro-B/pre-B cells

Bone marrow pro-B/pre-B cells were expanded after culture with recombinant murine IL-7 as previously described (2).

Cell cycle analysis

Sorted CD25+ B220+ cells were stained with propidium iodide after ethanol fixation and RNase treatment (2).

SDS-PAGE and Western blot analysis

In vitro IL-7 expanded populations of bone marrow pro-B/pre-B cells were harvested and lysed in detergent buffers as described (9) and electrophoresed on 4 to 12% SDS-PAGE gels under reducing conditions. Blotted and blocked nitrocellulose membranes were incubated with the hamster anti-{lambda}5 mAb FS1 (10) or with affinity-purified rabbit anti-actin IgG Ab and appropriate horseradish peroxidase-labeled secondary Abs. Membranes were developed by chemiluminescence and exposed to Hyperfilm (Amersham, Arlington Heights, IL).

RNA isolation and RT-PCR analysis

B-lineage cells were sorted from young and aged mice and pelleted, and polyadenylated mRNA were extracted using a Quick Prep Micro mRNA purification kit (Pharmacia Biotech, Piscataway, NJ) or sorted directly into TRIzol reagent (Life Technologies, Gaithersburg, MD) and total RNA extracted. RNA was reverse transcribed to cDNA with murine leukemia virus reverse transcriptase and amplified using the GeneAmp PCR kit with AmpliTaq DNA polymerase (Perkin-Elmer, Foster City, CA). PCR primers are specific for murine {lambda}5 (spanning exons 1 through 3 (11); (amplicon size, 361 bp) or for murine glyceraldehyde-3-phosphate dehydrogenase (G3PDH)3 cDNA (Clontech Laboratories, Palo Alto, CA; amplicon size, 452 bp). PCR amplification was performed with modified hot start for 30 cycles with 1 cycle consisting of 95°C for 2 min, 60°C for 2 min, and 72°C for 2 min, with 1 additional extension step at 72°C for 3 min. PCR products were Southern blotted, hybridized to gene-specific radiolabeled probes, and densitometrically quantitated.

Statistics

The significance of the results was evaluated by Student’s t test.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
The reduced numbers of pre-B cells in senescent mice could result from failure to generate new pre-B cells from the pro-B cell pool, reduced transition of early pre-B cells to later developmental stages, altered kinetics of transit through the pre-B compartments, and/or to limited expansion of these pre-B cell populations. To address this issue, we assessed not only pro-B cell but also both early (CD43+) and later stage (CD43-) pre-B cell populations in aged BALB/c mice. As shown in Figure 1GoA, CD43+CD25-B220low pro-B cells were only slightly reduced and early pre-B cells (CD43+CD25+B220+) were not significantly reduced in aged bone marrow. However, decreased numbers of both large and small CD43-CD25+B220low pre-B/B cells were seen in aged mice. CD43 (S7) has been shown to be expressed on B1 cells in the periphery (12) and aged mice have been reported to have increased numbers of B1 cells (13). To ensure that B cells were not contributing to CD43+ B-lineage populations, bone marrow from four aged mice identified as deficient in small pre-B/B cells and bone marrow from four young mice were depleted of B cells and reanalyzed for CD43, CD25, and B220 expression.



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  		FIGURE 1. Aged BALB/c mice exhibit loss of late stage pre-B cells, but retention of early pre-B cells. A, Bone marrow cells from 19 individual BALB/c mice at 3 to 6 mo of age and from 13 BALB/c mice at 24 to 29 mo of age were analyzed for surface CD43 (PE-S7), CD25 (biotin-D7/CyChrome streptavidin), and B220 (FITC-RA3-6B2). The percentage of total nucleated bone marrow cells for each population is shown. CD43+CD25-B220low cells are designated as pro-B cells, CD43+CD25+B220low cells are early pre-B cells, and CD43-CD25+B220low cells are designated as large and small pre-B/B cells. Dark symbols are for young mice; clear symbols for aged mice. In B, to eliminate B cells from the pre-B/B cell populations for flow cytometry analysis, bone marrow cells from four individual young (3-mo-old) and aged (22–24-mo-old) BALB/c mice were first panned on anti-IgM/IgG-coated plates and then stained and analyzed as in A. These aged mice were previously shown to have significantly decreased proportions of CD43- B220low bone marrow cells. *, data from the aged group are significantly different from the young group at p < 0.05.

 
As shown in Figure 1GoB, the proportion of surface Ig-CD43+CD25+B220low early pre-B cells was largely retained although proportions of Ig-CD43-CD25+B220low large and small pre-B cells were extensively reduced, results analogous to those obtained with unfractionated bone marrow cells (Fig. 1GoA). We conclude that pro-B cell and early pre-B cell formation occurs relatively normally in senescent BALB/c mice; however, the transition from nascent CD43+ pre-B cells to the CD43- pre-B cell compartments is rendered less efficient. Numbers of nucleated viable bone marrow cells were not statistically different between young and senescent BALB/c mice (young, 3.3 ± 0.9 x 107 cells; aged, 3.9 ± 1.2 x 107 cells per femur/tibia pair); therefore, alterations in the proportions of B-lineage cells seen in senescent BALB/c bone marrow also reflect changes in their absolute numbers.

Since the transition from early (CD43+) to later (CD43-) pre-B cell stages is dependent on expression of the pre-B cell receptor (µ/{lambda}5/VpreB) (5, 6, 7), decreased formation of pre-B cells in aged mice could result from diminished expression or function of the pre-B cell receptor complex. Expression of µ heavy chain in early pre-B cells appears unaffected by the aging process (data not shown); therefore, we have assessed the expression of the {lambda}5 surrogate light chain. As shown in Figure 2Go, CD43+B220low pro-B/early pre-B cells from young BALB/c mice exhibited both surface {lambda}5 staining and cytoplasmic {lambda}5 staining by the LM34 mAb, with 73 ± 9% (n = 10; range, 58–87%) of these B-lineage precursors expressing levels of cytoplasmic {lambda}5 protein staining above that seen with negative controls. In contrast, CD43+B220low pro-B/early pre-B cells present in senescent BALB/c mice generally expressed decreased surface and cytoplasmic {lambda}5 protein (55 ± 20% cytoplasmic {lambda}5+ (range, 13–85%), n = 12, with p < 0.05 when compared with values for young mice). Negligible {lambda}5 protein, either on the surface or within the cytoplasm, was detected among late stage CD43- B220+ pre-B/B cells.



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  		FIGURE 2. Decreased surface and cytoplasmic expression of {lambda}5 protein by aged B-lineage cells. BALB/c bone marrow cells from young 3- to 6-mo old BALB/c mice (A) and aged 22- to 29-mo-old BALB/c mice (B) were stained for CD43 (PE-S7) and B220 (FITC-RA3-6B2) as well as for {lambda}5 (biotin-LM34/CyChrome streptavidin). Staining for {lambda}5 was performed on intact cells (surface staining) or after fixation and permeabilization (cytoplasmic staining). The {lambda}5 staining for gated CD43-B220+ pre-B/B cells and CD43+B220+ pro-B/early pre-B cells is shown. Data are representative of 10 young and 12 aged BALB/c mice examined. Light lines are staining with secondary CyChrome streptavidin reagent alone.

 
As shown in Figure 1GoA, some aged mice have proportions of late stage B cell precursors which overlap those seen with young mice, while markedly lower levels of B cell precursors are clearly seen in other aged mice. Bone marrow cells from five aged mice which had "young-like" CD43-CD25+B220low small pre-B/B cell levels (4.9–12.6%; average, 7.7 ± 3.0%) exhibited staining for cytoplasmic {lambda}5 protein (62 ± 23%) in their CD43+ B220low pro-B/early pre-B cells which was not significantly different from that seen with young mice. In contrast, pro-B/early pre-B cells from five aged mice identified as having low pre-B/B cell proportions (0.4–1.4%; average, 1.0 ± 0.5%) had reduced staining for cytoplasmic {lambda}5 protein (41 ± 16%). Therefore, even within the aged mouse population, levels of cytoplasmic {lambda}5 protein in pro-B/early pre-B cells generally correlated with proportions of late stage B lineage precursor cells.

The decreased expression of {lambda}5 protein among senescent B lineage precursor cells in vivo was also seen under in vitro culture conditions. In vitro IL-7-expanded pro-B/early pre-B cells from both young and aged BALB/c mice were uniformly CD43+, BP-1+, and B220+; variably positive for CD25 (10–90%); and <=25% cytoplasmic µ chain+. Pro-B/pre-B cells from senescent BALB/c mice had {lambda}5 protein levels as determined by Western blot analysis which were generally decreased by two- to fourfold (Fig. 3Go).



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  		FIGURE 3. IL-7-stimulated pro-B/pre-B cells from aged BALB/c mice express decreased {lambda}5 protein. Bone marrow cells from 3- and 26-mo-old BALB/c mice were stimulated in vitro with IL-7 as described in Materials and Methods. Expanded populations of pro-B/pre-B cells were harvested 7 days after initiation of culture, and detergent lysates were prepared. Lysates from equivalent numbers (50, 25, 12.5, 6.25 x 104) of harvested pro-B/pre-B cells were separated by SDS-PAGE, Western blotted, and {lambda}5 protein detected with FS1 Ab and actin protein detected with rabbit anti-actin Ab with chemiluminescent development as described in Materials and Methods. Results are representative of 12 analogous experiments.

 
The relative levels of {lambda}5 mRNA were also determined, by semiquantitative RT-PCR, in ex vivo bone marrow cells from young and aged mice. In five aged mice tested, the levels of bone marrow {lambda}5 mRNA were significantly reduced when compared with young bone marrow cells (data not shown). When sorted populations of CD43+ B220+ pro-B/early pre-B cells as well as CD43-B220+ pre-B/B cells from senescent BALB/c mice were analyzed for {lambda}5 mRNA expression, levels of {lambda}5 mRNA were decreased by ~three- to fourfold (Fig. 4Go).



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  		FIGURE 4. Decreased {lambda}5 mRNA expression in aged B-lineage cells. Polyadenylated RNA was isolated from sorted bone marrow B lineage precursors as described in Materials and Methods. Polyadenylated RNA was prepared from 8.9 x 104 to 1.4 x 105 CD43+B220+ cells and from 3.3 x 105 to 1.3 x 106 CD43-B220+ cells from young and aged mice. One-fifth of the RNA sample was used for reverse transcription and one-fourth of the reverse transcriptase preparation was used for PCR with either {lambda}5 or G3PDH primers. Lane 1, Young (3 mo) CD43+B220+ pro-B/early pre-B cells; Lane 2, Young (3 mo) CD43-B220+ late stage pre-B/immature B cells; Lane 3, old (24 mo) CD43+B220+ pro-B/early pre-B cells; Lane 4, old (24 mo) CD43-B220+ late stage pre-B/immature B cells; Lane 5, 70Z/3 pre-B cells as positive control. Data are representative of sorted cell populations from one of two experiments. Densitometric scans of {lambda}5 bands were normalized to those of G3PDH.

 
The reduced expression of {lambda}5 surrogate light chains among pro-B/early pre-B cells would be anticipated to have substantial ramifications for B lymphopoiesis. Expression of {lambda}5 is not essential for development and maintenance of CD43+B220+ pro-B cells (14). Therefore, in senescent BALB/c mice, reduced {lambda}5 surrogate light chain expression would not be expected to dramatically alter pro-B/early pre-B cell numbers, consistent with our observations. However, given the importance of the pre-B cell receptor in the progression and expansion of early pre-B cells, population of the CD43- pre-B cell compartments in aged mice would be compromised if reduced {lambda}5 levels result in decreased assembly or surface expression of pre-B cell receptors.

We have also directly assessed the mitotic activity of the reduced population of large pre-B cells in aged mice. Sorted populations of large CD25+B220+ pre-B cells from five senescent BALB/c mice had 61 ± 7% of cells in S + G2-M, comparable with results obtained with sorted large CD25+B220+ pre-B cells from young mice (61 ± 4%, n = 4) (data not shown). Therefore, although decreased in number, the large pre-B cells in aged mice retain their characteristic high mitotic activity. We postulate that these pre-B cells probably express levels of pre-B cell receptors appropriate to provide the requisite signals for proliferation. Therefore, the decline in surrogate light chain expression may affect the numbers of nascent pre-B cells recruited into the highly mitotically active compartment, but not their capacity to undergo division.

While our hypothesis suggests that decreased {lambda}5 expression may ultimately affect the production of large and small CD43- pre-B cells in senescence, it is also possible that the decline in late stage B cell precursors seen in aged mice results from altered transit through the pre-B cell compartments or to enhanced emigration from the bone marrow to the periphery. However, recent kinetic studies suggest that the loss of late stage pre-B cells in aged mice reflects neither more rapid progression through the pre-B cell stage nor altered turnover rates among pro-B cells (15, 16). Previous studies have shown that surface {lambda}5 can be up-regulated on pro-B cells by culture with the supportive bone marrow stromal cell line, FLST2, together with IL-7 (10). Stromal cells isolated from senescent BALB/c mice have been shown to be poorer in their capacity to support the growth of pro-B cells in vitro (4), implying functional differences in stromal cells concomitant with the aging process. Alternatively, reduced responsiveness of B cell precursors from aged mice to stromal cell-derived signals may also contribute to poor surrogate light chain expression.


   Acknowledgments
 
We thank Dr. Norman R. Klinman, Scripps Research Institute, for his reading of the manuscript. We acknowledge James Phillips, Flow Cytometry Core Facility, Sylvester Comprehensive Cancer Center, for assistance with cell analysis and sorting and Kris Hudson, Karen Kamm, and Alim Ladha for excellent participation in some of the experiments.


   Footnotes
 
1 Supported by National Institutes of Health Grants RO1-AG13847 and RO1-AG15474 to R.L.R. and RO3-AG14892 to B.B.B. Back

2 Address correspondence and reprint requests to Dr. Richard L. Riley, Department of Microbiology and Immunology, P.O. Box 016960 (R-138), University of Miami School of Medicine, Miami, FL 33101. E-mail address: Back

3 Abbreviation used in this paper: G3PDH, glyceraldehyde-3-phosphate dehydrogenase. Back

Received for publication July 13, 1998. Accepted for publication August 18, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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