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The Journal of Immunology, 2001, 167: 5539-5542.
Copyright © 2001 by The American Association of Immunologists

Cutting Edge

Cutting Edge: Antigen-Driven Lymphocyte Recruitment to the Lung Is Diminished in the Absence of Urokinase-Type Plasminogen Activator (uPA) Receptor, but Is Independent of uPA1

Margaret R. Gyetko2, Sudha Sud, Joanne Sonstein, Timothy Polak, Anchal Sud and Jeffrey L. Curtis

Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, Ann Arbor Veterans Affairs Medical Center and University of Michigan Medical Center, Ann Arbor, MI 48109


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The requirement for urokinase plasminogen activator (uPA) and uPA receptor (uPAR) in T lymphocyte migration is unknown. uPA-/- mice have fewer pulmonary lymphocytes in response to certain infections, but its unknown whether this is due to diminished recruitment. Primed, recipient mice were IT inoculated with Ag. Three days later, fluorescently labeled lymphoblasts from background-matched control wild-type (WT), uPA-/-, or uPAR-/- donor mice were injected i.v., and their recruitment was determined. Approximately twice the number of uPA-/- compared with WT lymphoblasts were recruited to the lungs of WT recipients. This difference was eliminated when uPA-/- and WT lymphoblasts were injected into uPA-/- recipients. Thus, the reduced number of lung lymphocytes in infected uPA-/- mice is not due to reduced recruitment. However, uPAR is critically involved in recruitment. Markedly fewer uPAR-/- compared with WT lymphoblasts were recruited to the lung. These findings suggest that uPAR may be a novel target for immune modulation in T lymphocyte-mediated disorders.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
We have shown that urokinase plasminogen activator (uPA)3-/- mice have markedly reduced numbers of pulmonary T cells in response to pulmonary Cryptococcus neoformans and Pneumocystis carinii infection, and have impaired lymphocyte-mediated host defense against these pathogens (1, 2). However, it is not clear whether the decreased lymphocyte number is due to diminished recruitment or to diminished lymphocyte proliferation/activation in the lung and regional lymph nodes. The requirement for uPA and uPA receptor (uPAR) in lymphocyte migration in vivo is unknown.

The expression of uPA and uPAR are activation events in T lymphocytes. Resting T lymphocytes do not express uPAR, and only low levels of uPA are detected. TCR-mediated stimulation or stimulation with phorbol esters substantially up-regulates both uPA and uPAR in T cells (3, 4). uPAR is coexpressed with IL-2R (CD25). Because CD25 expression is critical during T lymphocyte activation, the coexpression of uPAR with CD25 suggests that uPAR may also play a role in these processes (3). Further, uPAR is up-regulated by exposure to IL-2 and IL-4, cytokines importantly involved in T lymphocyte activation, but not to several other cytokines (3).

There is substantial evidence that uPA and uPAR are critically involved in cellular migration. Leukocytes express uPA (5, 6, 7, 8) and also specific receptors for uPA on the cell surface (9, 10). uPA converts the inactive proenzyme plasminogen to plasmin, a protease of broad substrate specificity (11). uPAR clusters to the leading front of cellular migration, thus focusing the proteolytic activity of uPA in the direction of migration (12). Chemotaxis is profoundly reduced in monocytes treated with antisense-uPAR oligonucleotides or anti-uPAR Abs, which demonstrates the critical role that uPAR plays in migration in these cells. Although Abs against the catalytic domain of uPA have no effect on monocyte chemotaxis, treatment with antisense-uPA oligonucleotides is inhibiting, suggesting that uPA binding to its receptor may be involved in cell movement (12). In vitro support of the role of uPA in cell migration has been demonstrated in tumor cells, in which migration can be impeded by inhibitors to uPA or plasmin (7, 13, 14).

Lung lymphocyte enumeration provides only a steady-state picture of the balance between influx and proliferation on one hand and cell removal on the other. To address influx directly, we have established a specific assay of Ag-driven lymphocyte recruitment to the lung by determining the arrival of fluorescently labeled lymphoblasts using flow cytometry (15). This SRBC model is highly reproducible and well described, and occurs rapidly (16, 17, 18). Using this model we were able to determine the requirement for uPA and uPAR in lymphocyte recruitment to the lung during immune responses.


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

Mice were housed in specific pathogen-free isolation rooms in the University of Michigan Department of Laboratory Animal Medicine (Ann Arbor, MI), which is fully accredited by the American Association for Accreditation of Laboratory Animal Care. All procedures were approved by the animal care committees of the Veterans Administration and the University of Michigan Committee on Use and Care of Animals.

Transgenic uPAR-/- mice, uPA-/- mice, and background-matched control wild-type (WT) mice were generous gifts from Dr. P. Carmeliet (Leuven, Belgium). These mice were developed as previously described (19, 20). Genotype of the uPA-/-uPAR-/-, and WT mice was confirmed by PCR or RT-PCR analysis as described previously (1, 20). Mice of this background (C57B6/129) are immunocompetent (21, 22).

Animal model

A secondary pulmonary immune response was induced in primed mice by intratracheal (IT) challenge with SRBC (sheep no. 4158; Colorado Serum, Boulder, CO), as described previously (23). Briefly, mice were primed by i.p. injection of SRBC. Two to three weeks later, 5 x 108 SRBC in 0.05 ml of saline were instilled by IT injection, resulting in a reproducible, CD4-dependent pulmonary immune response (24). Mice were killed by sodium pentathal overdose at the indicated times, and lung tissue was harvested.

Ex vivo lymphocyte expansion

Spleens and lymph nodes were harvested from mice and lymphocytes expanded as described previously (15).

CMFDA labeling and infusion of lymphocytes

As previously described (15), the cultured T lymphoblasts were resuspended at 2 x 107 cells/ml in 500 nM 5-chloromethylfluorescein diacetate (CMFDA) (Molecular Probes, Eugene, OR), washed, and resuspended in sterile saline. CMFDA-labeled cells (2 x 107) in 0.2 ml of saline were injected into the tail veins of SRBC-primed and IT-challenged mice. This labeling method permits the separation of cell fragments or dead cells from live intact cells by flow cytometric analysis.

Leukocyte collection and purification

As described previously (23), lungs were perfused, lavaged, minced, and incubated with collagenase IA (Sigma-Aldrich, St. Louis, MO) and 0.01% DNase type 1 (Sigma-Aldrich) in PBS (23). The resulting single cell suspension was used for assay. For each sample, 100,000 events were collected and analyzed using a FACScan and CellQuest analysis program (BD Immunocytometry Systems, San Jose, CA). The absolute number of labeled cells per lung was calculated by multiplying the percentage of CMFDA-labeled cells by the total leukocyte count in a given sample.

Staining for selectin ligand expression and cell surface markers

Selectin ligand expression was determined as previously described (15). Briefly, lymphoblasts were incubated with either murine selectin/human IgM or murine CD45/human IgM chimeric protein and stained with biotinylated goat anti-human IgM secondary Ab (Zymed Laboratories, South San Francisco, CA) and streptavidin/phycoerythrin conjugate (BD PharMingen, San Diego, CA), fixed, and stored at 5°C. Staining for other cell surface markers, including CD11a (clone 2D7), CD18 (clone C71/16), CD54 (clone 3E2), CD49d (clone R1-2), CD44 (clone Pgp-1), and CD45 (clone 30-F11) (BD PharMingen), was conducted in essentially the same manner. Samples were read by flow cytometry and analyzed using the CellQuest analysis program (BD Immunocytometry Systems). The CD45/IgM chimera showed the same low level of binding to cells as the selectin/IgM chimeras in the presence of EDTA. This nonspecific reactivity was used to set the threshold for a positive reaction as detailed previously (16).

Statistical analysis

Comparisons among group means were performed by unpaired Student’s t test. Where appropriate, data were log-transformed to ensure equivalent variances among groups. Statistical calculations were done using StatView 4.5 software (Abacus Concepts, Berkeley, CA). Value of n = number of mice in each experimental group. Data are expressed ± SEM. Statistical difference was accepted at p <= 0.05.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
To determine whether uPA is required for lymphocyte recruitment to the lung, lymphoblasts were generated from donor WT and uPA-/- mice. Recipient WT mice were primed and IT rechallenged with SRBC. Equal numbers of either WT or uPA-/- lymphoblasts were infused i.v. into the WT recipients 3 days post-SRBC IT rechallenge, the time of maximal pulmonary inflammatory responses (15). Eighteen hours later, the lungs were processed to a single-cell suspension and analyzed by flow cytometry, and the absolute number of CMFDA+ cells and the percentage of CMFDA+ cells in the samples were determined. Surprisingly, as shown in Fig. 1Go, more than twice the number of uPA-/- lymphoblasts were recruited to the lungs of WT mice than were WT lymphoblasts, with comparable increases in percentage of CMFDA+ lymphoblasts in the uPA-/- mice (p <= 0.002 and p <= 0.001, respectively; n = 5). uPA has previously been shown to either enhance or be irrelevant to cellular migration, depending on the model used (7, 12, 13, 14, 25); there is no precedence for an absence of uPA-enhancing migration. In the above experiment, although the donor uPA-/- lymphoblasts were deficient in uPA, the WT recipient animals were not. Because the recipient mice were at the height of a pulmonary immune response at the time of lymphoblast infusion, it is highly likely that the recipients had increased uPA levels, because virtually all the cytokines involved in immune responses up-regulate uPA expression (6). Because there is evidence that uPA binding to uPAR can rapidly transduce activation signals (26, 27), we reasoned that the uPAR-expressing uPA-deficient lymphoblasts bound the WT recipient’s uPA, thus becoming uPA replete and potentially activated.



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  		FIGURE 1. Comparison of recruitment of WT and uPA-/- lymphoblasts to the lungs of WT recipient mice. WT or uPA-/- CMFDA-labeled lymphoblasts were i.v. infused into SRBC-primed WT mice 3 days after they were inoculated with SRBC IT. Eighteen hours later the number and percentage of CMFDA+ lymphocytes recruited to the lungs of the WT recipient mice were determined. WT lymphoblasts are represented by the filled bars and uPA-/- lymphoblasts are represented by the hatched bars. Data are expressed as mean ± SEM. *, p <= 0.002; n = 5.

 
To test this possibility, we repeated the study using uPA-/- recipients. This design completely eliminates uPA from the uPA-/- recipient/uPA-/- donor combination, while allowing lymphoblast uPA production in the uPA-/- recipient/WT donor combination. Preliminary experiments confirmed that uPA-/- recipients generated acceptable levels of immune-mediated pulmonary inflammation. Primed, IT-rechallenged uPA-/- mice increased their T lymphocyte percentage in bronchoalveolar lavage from an unchallenged baseline of 0.6–41% (0.94 ± 0.12 x 106) on day 3 post-IT, a level comparable to WT mice (0.5% baseline to 45%, 1.22 ± 1.13 x 106). Moreover, histologic analysis showed comparable degrees of lung inflammation in uPA-/- and WT recipients (data not shown).

uPA-/- recipients were SRBC primed and IT rechallenged. uPA-/- and WT lymphoblasts were infused i.v. into the uPA-/- recipients 3 days post-SRBC IT rechallenge. Eighteen hours later the absolute number of CMFDA+ cells and the percent of CMFDA+ cells in the samples were determined as above. As shown in Fig. 2Go, uPA-/- and WT lymphoblasts were recruited equally well to the lungs of uPA-/- mice both in terms of the absolute numbers of CMFDA+ cells and the percent of CMFDA+ cells.



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  		FIGURE 2. Comparison of recruitment of WT and uPA-/- lymphoblasts to the lungs of uPA-/- recipient mice. WT or uPA-/- CMFDA-labeled lymphoblasts were i.v. infused into SRBC-primed uPA-/- mice 3 days after they were inoculated with SRBC IT. Eighteen hours later the number and percentage of CMFDA+ lymphocytes recruited to the lungs of the uPA-/- recipient mice were determined. WT lymphoblasts are represented by the filled bars and uPA-/- lymphoblasts are represented by the hatched bars. Data are expressed as mean ± SEM. Value of p = NS; n = 5.

 
From these data, we conclude that lymphocyte recruitment to the lung is independent of uPA, as complete elimination of uPA from the model resulted in recruitment that was identical to the recruitment of WT lymphoblasts. Therefore, the previously described diminution of lymphocyte cell number in response to pulmonary C. neoformans and P. carinii infection cannot be explained by diminished lymphocyte recruitment.

Our previous in vitro work has demonstrated that uPAR plays an obligate role in monocyte and neutrophil chemotaxis (12, 25). The importance of uPAR in cell migration has been extended to other cell types, including endothelial cells, breast carcinoma, and smooth muscle cells, among others (28, 29, 30). In vivo leukocyte recruitment is far more complex than chemotaxis, due, in part, to the variety of adhesion molecules that must be sequentially used. Despite this, uPAR has been shown to be required for leukocyte recruitment to the lung in response to Pseudomonas aeruginosa pneumonia and to the peritoneal cavity in response to thioglycolate (31, 32). The role of uPAR in lymphocyte recruitment in vivo is unknown. Therefore, we sought to determine whether uPAR played a role in lymphocyte recruitment to the lung.

WT recipients were SRBC primed and IT rechallenged. uPAR-/- and WT lymphoblasts were infused i.v. into the WT recipients 3 days post-SRBC IT rechallenge. Eighteen hours later the absolute number of CMFDA+ cells and the percentage of CMFDA+ cells in the samples were determined as above. As shown in Fig. 3Go, fewer than half (40.2%) the number of uPAR-/- lymphoblasts were recruited to the lungs of WT mice than were WT lymphoblasts, with comparable decreases in the percentage of CMFDA+ uPAR-/- lymphoblasts (49.6%) recruited (p <= 0.007 and p <= 0.049, respectively; n = 6). We eliminated potential differences in cell surface expression of adhesion molecules by WT and uPAR lymphoblasts as an explanation for diminished uPAR lymphoblast recruitment. WT and uPAR-/- lymphoblast expression of CD11a, CD18, CD54, CD49d, and CD44, as well as P- and E-selectin ligands were found to be the same (data not shown). Thus, uPAR expression is an important determinant in lymphocyte recruitment to the lung.



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  		FIGURE 3. Comparison of recruitment of WT and uPAR-/- lymphoblasts to the lungs of WT recipient mice. WT or uPAR-/- CMFDA-labeled lymphoblasts were i.v. infused into SRBC-primed WT mice 3 days after they were inoculated with SRBC IT. Eighteen hours later the number and percentage of CMFDA+ lymphocytes recruited to the lungs of the WT recipient mice were determined. WT lymphoblasts are represented by the filled bars and uPAR-/- lymphoblasts are represented by the hatched bars. Data are expressed as mean ± SEM. *, p <= 0.05; **, p <= 0.007; n = 6.

 
Lymphocyte recruitment to the lung is an area of intense interest because individual lymphocytes are short-lived cells that are susceptible to apoptosis and have limited intrapulmonary capacity to proliferate (33, 34). Thus, ongoing recruitment is required for immune-mediated pulmonary defenses. We have found that the P- and E-selectin ligands and the {alpha}4 integrin chain (CD49d) expressed on the lymphocyte surface mediate inflammation-dependent T lymphoblast trafficking into the lung in a largely independent manner (15). CD49d with {beta}1 forms the VLA-4 integrin, and CD49d with {beta}7 forms the homing receptor for Peyer’s patches (35). Ab blockade of {alpha}4 resulted in an ~50% decrease in lymphoblast recruitment, and genetic elimination of P- and E-selectin ligands alone caused an ~60% decrease. {alpha}4 blockade together with genetic elimination of selectin ligands resulted in a combined reduction of ~85% (15). Because elimination of uPAR results in a >50% reduction in lymphoblast recruitment, it is unlikely that uPAR acts by an independent mechanism. uPAR interacts with a variety of cell proteins, forming complexes with the {beta}1, {beta}2, and {beta}3 integrins and other signaling proteins, such as src kinases and caveolin (36, 37, 38). Functionally, uPAR is a potent modulator of {beta}2 integrin function (12, 31, 32, 38, 39). Therefore, it is conceivable that uPAR is modulating either selectin binding or function of the {alpha}4 integrin in this model. Neutrophil uPAR has recently been shown to associate with L-selectin on the cell surface, although the functional significance of this is not known (40). Because we have shown that Ab blockade of L-selectin on the lymphocyte cell surface had no effect on lymphocyte recruitment to the lung in this model (17), uPAR-mediated modulation of L-selectin function is an unlikely mechanism for diminished recruitment of uPAR-/- lymphoblasts.

In summary, we have demonstrated that uPAR expression is an important modulator of lymphocyte recruitment to Ag-inflamed lung. The absence of uPAR expression results in a >50% reduction of lymphocyte recruitment. This function of uPAR is independent of its natural ligand, uPA. Thus, the decreased lung lymphocyte numbers previously described in infected uPA-/- mice is unlikely to be due to reduced recruitment, but rather to a previously demonstrated reduced lymphocyte activation and proliferation (41). This is the first study demonstrating a role for uPAR in lymphocyte recruitment in vivo. These findings suggest that uPAR may be a novel target for immune modulation in T lymphocyte-mediated disorders.


   Acknowledgments
 
We thank Peter Carmeliet for generously providing the uPA-/-, uPAR-/-, and background-matched WT mice; and Lloyd M. Stoolman and Ronald A. Craig for the selectin chimeras.


   Footnotes
 
1 This work was supported by Merit Research grants and Research Enhancement Award Program funds from the Department of Veterans Affairs (to M.R.G. and J.L.C.), and by National Institutes of Health Grants HL60620 (to M.R.G.), HL61577, and HL56309 (to J.L.C.). Back

2 Address correspondence and reprint requests to Dr. Margaret R. Gyetko, Ann Arbor Veterans Affairs Medical Center and University of Michigan Medical Center, 3916 Taubman Center, Medical Center Drive, Ann Arbor, MI 48109-0360. E-mail address: mgyetko{at}umich.edu Back

3 Abbreviations used in this paper: uPA, urokinase plasminogen activator; uPAR, uPA receptor; CMFDA, 5-chloromethylfluorescein diacetate; WT, wild-type; IT, intratracheal(ly). Back

Received for publication July 30, 2001. Accepted for publication September 24, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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