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Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523
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Abstract |
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Introduction |
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10% develop a chronic or latent state of infection that will last for the rest of their lives (1). Macrophages, granulocytes, and dendritic cells in the lungs represent the first line of defense against pathogens entering the lungs. Among these, dendritic cells are clearly a key population because of their ability to transport and present Ags to naive T cells in the secondary lymphoid organs, thus initiating adaptive immunity (2, 3). In addition, other cells of the macrophage/monocyte lineage are recruited into the developing granuloma, where they surround the sites of infection and control and contain the surviving bacteria after receiving appropriate activating signals from Th1 CD4 T cells (4, 5, 6, 7).
Just as the T cell response to tuberculosis is complex (7, 8), it is now apparent that the overall macrophage response is a dynamic event. To date, however, the kinetics of the macrophage response has not been clearly defined. The growing availability of Abs to macrophage cell surface markers, coupled with an improved understanding of how expression of these markers changes, particularly those expressed by dendritic cells, now allows a better definition of these events.
In the present study, flow cytometry was used to define the influx of cells into the lungs during the early stage of pulmonary M. tuberculosis infection. Based on expression of the cell surface markers, several distinct populations of macrophages, as well as granulocytes and NK cells, could be distinguished. In addition, maturation of incoming dendritic cells could be identified as the immune response to the infection developed. Interestingly, markers of activation on these cell populations that were evident during the early phase of the infection were observed to be lost at a much later time point when the lung infection is thought to be in some form of latent state (4). Taken together, the data show that during the course of pulmonary M. tuberculosis infection, there is activation of macrophages and dendritic cell populations during the early phase that are associated with development of an effective immune response; however, during the chronic phase of infection these cell populations were not activated and resulted in down-regulation of the immune response.
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Materials and Methods |
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Specific pathogen-free female C57BL/6 mice (The Jackson Laboratory, Bar Harbor, ME) at 6–8 wk old were used. They were housed under barrier conditions in a level III biosafety facility and were allowed free access to sterile chow and water.
Experimental infections
M. tuberculosis, Erdman strain (TMCC 107), was grown from low-passage seed lots in Proskauer-Beck liquid medium containing 0.02% Tween 80 to mid-log phase, then aliquoted and frozen at -70°C until use. Mice were infected aerogenically with the Erdman strain of M. tuberculosis by using a Glas-Col aerosol generation device (Glass-Col, Terre Haute, IN) as previously described (9) to result in the deposition of 200 bacilli within the lungs.
Preparation of bronchoalveolar lavage (BAL) 4 and lung cell suspensions
Mice were euthanized and the pulmonary cavities were opened. After severing the descending aorta, the blood in the lungs was cleared by perfusion through the right heart with 5 ml of PBS containing 50 U of heparin (Sigma-Aldrich, St. Louis, MO) per ml until the lungs became whitish. Using an 18-gauge needle, the trachea was cannulated, and 1 ml of heparin/PBS was slowly injected into the lungs and then withdrawn. This procedure was repeated 7–10 times, and a total of 5–8 ml of lavage fluid was collected.
To obtain lung cell populations, the lungs were perfused with heparin solution as above. Thereafter, they were aseptically removed and cut into small pieces. The dissected tissue was incubated in RPMI medium (RPMI 1640 (Life Technologies, Gaithersburg, MD) supplemented with 1% glutamine (Sigma-Aldrich), 0.1 mM nonessential amino acids (Life Technologies), 50 µM 2-ME (Sigma-Aldrich), and 1% penicillin-streptomycin (Sigma-Aldrich)) containing collagenase XI (0.7 mg/ml; Sigma-Aldrich) and type IV bovine pancreatic DNase (30 mg/ml; Sigma-Aldrich) during 30–45 min at 37°C. The action of the enzymes was stopped by adding 10 ml of RPMI medium containing 10% FBS (cRPMI), and digested lungs were further disrupted by gently pushing the tissue through a nylon screen (70 µm). The single-cell suspension was then washed and centrifuged at 200 x g. To lyse contaminating RBCs, the cell pellet was incubated during 5 min at room temperature with 5 ml of Gey’s solution (NH4Cl and KHCO3). Cells were then washed with cRPMI and resuspended in 2 ml of cRPMI.
Single-cell suspensions obtained by enzymatic digestion as indicated above were washed in deficient RPMI (Irvine Scientific, Santa Ana, CA), which was supplemented with 1% L-glutamine (Sigma-Aldrich), 1% HEPES (Sigma-Aldrich), 0.1% sodium azide (N3Na; Sigma-Aldrich), and 2% FBS. The cells were stained during 30 min at 4°C with directly conjugated Abs. mAbs specific for CD11c (clone HL3, hamster IgG1), CD11b (Mac-1, clone M1/70, rat IgG2a), Gr-1 (clone RB6-8C5, rat IgG2b), CD3e (clone 145-2C11, hamster IgG1), CD45RB/B220 (clone RA3-6B2, rat IgG2a), NK-1.1 (clone PK136, mouse IgG2a), CD16/CD32 (clone 2.4G2, rat IgG2b), CD40 (clone 3-23, rat IgG2a), CD80 (clone 16-10A1, hamster IgG), CD86 (clone GL1, rat IgG2a), I-A/I-E MHC class II Ag (clone 2G9, rat IgG2a), rat IgG2a, rat IgG2b, rat IgG1, mouse IgG2a, and hamster IgG were purchased from BD PharMingen (San Diego, CA) or eBioscience (San Diego, CA) as direct conjugates to FITC, PE, PerCP, PerCP-cyanine 5.5 (PerCP-Cy5.5), or allophycocyanin. Purified rat anti-mouse CD16/CD32 mAb (mouse Fc-Block) was also purchased from BD PharMingen and used to prevent nonspecific binding of Abs to the Fc receptors. mAb F4/80 (clone CI:A3-1, rat IgG2b) as a direct conjugate to FITC was purchased from Serotec (Raleigh, NC). Cell acquisition was performed with a dual-laser flow cytometer (FACSCalibur; BD Biosciences, Mountain View, CA). Compensation of the spectral overlap for each fluorochrome was done gating in the R3 region and using CD11b Ag. The data were analyzed using CellQuest software (BD Biosciences).
Cell sorting
The lungs were enzymatically digested as indicated above, and the single cell suspension obtained was labeled with FITC-conjugated CD11b and PE-conjugated CD11c Abs. Lymphocytes and macrophages were gated according to their sizes and granularity defined in the forward light scatter (FSC) and side light scatter (SSC) plot. Cell populations were sorted based on their CD11b/CD11c profiles using a MoFlo flow cytometer/cell sorter (DakoCytomation, Fort Collins, CO). The CD11b-/ CD11c+/high, CD11b+/CD11c+/high, CD11b+/high/CD11c-, CD11b+/mid/CD11c-, and CD11b+/mid/CD11c+/low cell populations in macrophage area (R3) were sorted and, in the same manner, the CD11b+/low/CD11c- and CD11b+/mid/CD11c- cells were also sorted in the lymphocyte area (R2). To obtain higher purity of cell population, an enrichment mode was performed previously to the purified mode sort.
Cell morphology and microscopic examination
Sorted cell suspensions were cytospun onto glass slides (Shandon Instruments, Sewickley, PA) and were stained using the Hema 3 stain set (Biochemical Science, Swedesboro, NJ). Cell morphology was determined by microscopic examination.
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Results |
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Cells in the BAL fluid from naive mice and mice challenged 21 days previously with M. tuberculosis (Fig. 1) were analyzed according to their FSC and SSC characteristics by flow cytometry as well as for their expression of CD11b and CD11c (Figs. 1 and 2). Cells that clustered as FCSlow/SSClow were gated as regions R1 and R2 and were found to be mainly CD3+ (Figs. 2 and 3). Cells defined as FSChigh/SSChigh were gated as R3 and were shown to be CD11b-/CD11c+ (Fig. 1). Most cells (90–95%) in the BAL fluid from naive mice had this latter expression pattern and had typical morphology of macrophages and immature dendritic cells (data not shown). Cells in Fig. 1B defined as CD11b+/CD11c- were also positive for Gr-1 expression (Fig. 1C), indicating that they were granulocytes.
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Similar flow cytometric studies were performed using cells released from the lung tissues by enzymatic digestion. The FSC/SSC profile of these cells from naive mice resolved into two dense cell populations: an FSClow–mid/SSClow area (R1 and R2) and cells that were FSCmid–high/SSCmid–high, designated region R3 (Fig. 2A). As above, CD11c+ alveolar macrophages obtained by this method were located in R3 (Fig. 2).
The FSClow–mid/SSClow region of lung cells from naive mice was further subdivided into R1 and R2 regions (Fig. 2A, left and right, respectively). In the R2 area, cells were CD3+ (42%; Fig. 3A), NK1.1+ (8%; Fig.3B), or B220+ (33%; data not shown). Only a few Gr-1+ cells (0.9%) were located in the R2 area (data not shown). Approximately 23% of cells in the R2 region stained positive for CD11b+ (Fig. 3A), and among those 8% were NK1.1+/CD11blow and another 8% were NK1.1-/CD11b+/high (Fig. 3B). Furthermore, CD11b+ cells in the R2 region could be subdivided into NK1.1+ and NK1.1- cells (Fig. 3B). The CD11b+/NK1.1+ were further characterized as lacking expression of F4/80 and were CD11c+/low (Fig. 3B, panels 1 and 2). In contrast, CD11b+/NK1.1- cells were F4/80+/mid and CD11c- or CD11c+/mid (Fig. 3B, panels 3 and 4).
Cells in the R3 region could be separated into six distinct cell populations according to their expression of CD11b and CD11c (Fig. 4, A and C). These populations comprised of CD11b-/CD11c+/high cells (R5), CD11b+/CD11c+/high (R6), CD11b+/mid/CD11c+/mid (R7), CD11b+/mid/CD11c- (R8), CD11b+high/CD11c- (R9), and CD11b-/CD11c- (Fig. 4, A and C)
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Phenotypic characterization of lung cell populations by flow cytometry was used to conduct high-speed cell sorting of each population and further examination of morphology by microscopy. The dot plots for each sorted population are shown in Fig. 5. The percentage of positive cells in the CD11b/CD11c dot plot and the purity obtained after sorting each cell population were 9% positive and 91% purity for CD11b-/CD11c+/high (R5), 1% and 56% for CD11b+/CD11c+/high (R6), 3% and 62% for CD11b+/mid/CD11c+/mid (R7), 6% and 88% for CD11b+/mid/CD11c- (R8), and 2% and 85% for CD11b+/high/CD11c- (R9), respectively. The morphology of the cells in the R5 gate was that of alveolar macrophages, and these were identical with cells obtained in the BAL fluid. This R5 region also contained some small veiled cells that resembled immature dendritic cells in this sorted population. Most cells sorted from the R6 region had morphology typical of dendritic cells, with large lateral nuclei and very long cytoplasmic processes. Sorted cells from R6 also contained some neutrophils characterized by multilobed nuclei. Cells in R7 and R8 were smaller cells in comparison with those in R5 and R6 and had the morphology of monocytes, with typical horseshoe-like nuclei or small macrophages. Cells in the R9 region were neutrophils with the same morphology as indicated above (Fig.5).
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Changes in the phenotype and composition of cells in the lung were monitored from day 3 to day 21 after pulmonary challenge with M. tuberculosis. Cells in the R2 region were composed mainly of lymphocytes and monocytes, and these increased in number over this period of time as reported previously (10).
As indicated above, cells in the R3 region could be separated into six distinct cell populations according to their expression of CD11b and CD11c (Fig. 4). Fig. 4 compares the CD11b/CD11c profile from naive cells and cells harvested during the early stage (21 days) of the infection. The total number of cells defined as CD11b-/CD11c+/high (R5), CD11b+/CD11c+/high (R6), and CD11b+/mid/CD11c+/mid (R7) increased as a result of the infection (Fig. 4, A and B).
Increased expression of costimulatory and activation surface molecules on macrophage cell populations during the early stage of infection with M. tuberculosis.
Macrophages, monocytes, and dendritic cells have different constitutive levels of costimulatory and activation markers. It is well established that differentiated naive dendritic cells are the most efficient APCs, in contrast with macrophages and monocytes, because they constitutively express high levels of costimulatory molecules (CD80 and CD86), CD40, and class II MHC Ags on their cell surface (2, 3). Therefore, from the CD11b/CD11c dot plot shown in Fig.4C, we analyzed differential expression of CD80, CD86, CD40, and class II MHC Ags on the surfaces of the cells in each region. Cells in regions R5, R6, R7, R8, and R9 were gated, and the mean fluorescence channel (MFC) for each marker was compared with the MFC from the other regions (Table II). As shown, the R6 region, which contained CD11b+/high/CD11c+/high dendritic cells, had the highest constitutive expression of CD86, class II MHC, and CD40 Ags. CD80 Ag expression on cells within the naive population was similar on cells in regions R5 and R6. In addition, the CD11b+/mid/CD11c- (R8) cells gated from the R3 region were F4/80 positive (data not shown). The cells in R9 gate and 20% of cells in the R6 gate expressed Gr-1, were negative for costimulatory Ags, and had morphology typical of granulocytes (Fig. 5).
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Table III shows the changes in the percentages of cells for each cytometric gating region at a time point well into the chronic or latent stage of the disease, compared with the early response. The percentage of alveolar macrophages in region R5, defined as CD11b-/CD11c+, decreased from 20% in naive mice to 16% and 6% during the early or chronic stage of infection, respectively. In contrast, dendritic cells in R6 defined as CD11b+/high/CD11c+/high increased from 1% in naive to 7% and 4% during the early or chronic stage of infection, respectively. Monocytes and small macrophages in R7 defined as CD11b+/mid/CD11c+/mid increased about twofold as a result of infection, as did cells in R8. Neutrophils in R9 increased from 4% in the early infection to 14% during the chronic phase, consistent with increasing lung damage occurring at this time (11).
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Fig. 6 shows the relative up-regulation for each cell population in the CD11b/CD11c dot plot for CD86, CD80, CD40, and class II MHC Ags during the course of the infection with M. tuberculosis. The ratio between the average of MFCs (n = 4) for each of these Ags on the defined cell populations from the early stage and those for cells harvested during chronic stage of infection was determined vs the naive population, respectively. As shown in Fig. 6, the ratio for each Ag (except CD80) was higher during the early phase, as would be anticipated. In contrast, ratios of 1:1 were seen on cells harvested during the chronic phase, indicating that dendritic cells and macrophages present at this time were less activated and were not expressing MHC molecules at levels higher than that seen in age-matched naive controls.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Changes in surface expression of CD11b and CD11c allow some speculation as to the differentiation pathways of macrophages entering the lungs in response to the infection. The data suggest that CD11b+/mid/CD11c- monocytes are recruited into the lungs, where they increase their expression of CD11c and become CD11b+/mid/CD11c+/mid, thus potentially constituting the precursor cells for lung interstitial macrophages, alveolar macrophages, and dendritic macrophages. It is known that these cells terminally differentiate into macrophages or dendritic cells within the lungs and that this process depends greatly upon the local cytokine environment, particularly GM-CSF (12).
Based upon our data, it is possible that two separate pathways of differentiation may occur. In the first, CD11b-/CD11c+/high alveolar macrophages or immature dendritic cells located in the alveolar spaces may be activated by the presence of the infection and increase their expression of CD11b, becoming CD11b+/high/CD11c+/high activated macrophages or differentiated dendritic cells. The second pathway of differentiation that may occur within the CD11b+/mid/CD11c+/mid population is up-regulation of CD11b and CD11c markers, becoming the differentiated CD11b+/high/CD11c+/high dendritic cells observed in region R6.
The data also demonstrate that costaining with CD11b and CD11c allows a more precise definition of the cell subsets. To date, several reports (13, 14, 15, 16) have used CD11c+ staining as the sole marker to identify dendritic cells without taking into account that this marker is also expressed on alveolar macrophages. In addition to these latter cells, we found that the BAL also contained some small veiled cells that morphologically resembled immature dendritic cells, consistent with previous reports (17, 18). Moreover, whereas lymphocytes clustered as a dense region in the FSClow/SSClow (R2) area, this region also contained 23% of cells that stained CD11b+ and in addition for F4/80, a marker of monocyte/macrophage lineage cells (19).
Additional characterization of cells in these regions using expression of costimulatory Ags (CD80 and CD86), CD40, and class II MHC Ags, together with morphological characterization of sorted cell populations showed that CD11b-/CD11c+/high (R5) cells were a mixture of alveolar macrophages and early immature dendritic cells, whereas CD11b+/CD11c+/high (R6) cells were mainly differentiated dendritic cells and some activated macrophages. As discussed above, we speculate that alveolar macrophages or immature dendritic cells contained in the R5 gate may differentiate into activated macrophages or dendritic cells located in the R6 region. In fact, sorting of CD11b-/CD11c+/high cells from both the lung digests and BAL showed the morphology of alveolar macrophages, and treatment of these cells with LPS triggered them to change their phenotype to CD11b+/mid/CD11c+/high (data not shown).
Cells in the R6 region expressed high levels of CD80, CD86, CD40, and class II MHC and had the typical morphology of differentiated dendritic cells. After infection, a significant increase in CD40 expression occurred, and this could be observed as early as day 7. Notably, however, up-regulation of class II MHC was observed, but not to the extent that might have been anticipated (Table II and Fig. 6). This may reflect some degree of inhibition of Ag presentation caused by the bacterium itself or mycobacteria Ags, as several laboratories have recently noted (20, 21, 22, 23).
As verified by cell sorting, the R9 region was represented by neutrophils. Using conventional microscopy it is usually difficult to find neutrophils in the very early stages of the lung infection, but the data shown here verify that this population of cells does indeed enter the lungs early. As noted elsewhere (11), depletion of these cells seems to cause a transient drop in resistance early in the infection.
Based upon these observations, we also examined macrophage populations harvested from mice well into the chronic or latent phase of the infection. What was notable that increased expression of markers associated with activation and Ag presentation was not apparent on the macrophage subsets present at this later stage of the infection. The status of events during this stage of the disease is still poorly understood, both at the bacterial and host response levels. The data imply that fresh monocytes are still entering the granulomatous lesions at this later time, but they may not be differentiating further. Ag presentation appears completely shut down, which may simply reflect the fact that Ag is not being produced by bacteria because they are in a latent state, or that Ag presentation is being actively interfered. The latter is supported by our results in which APCs in the lung during the chronic stage of M. tuberculosis infection did not have the activated phenotype required to present Ag to T cells. These data are in accordance with previous reports indicating that cultured cells infected with M. tuberculosis resulted in defective Ag processing because of several factors, from down-regulation of cell surface expression of MHC class II Ags (21) and defective trafficking of immature class II molecules (20, 24, 25), to interferences of M. tuberculosis with the cellular transcriptional pathways that are activated by IFN-
(26), to specific action of lipoproteins from the mycobacterial lysate with Ag processing (20). In addition, it is also known that the local cytokine environment at this time includes cytokines such as IL-6, IL-10, and TGF
, which are down-regulatory (27, 28, 29). As we have recently suggested, accumulation of IL-10 may directly trigger reactivation disease (30).
In summary, flow cytometric analysis centering on the identification of the levels of expression of the CD11b and CD11c markers can be used to distinguish between subsets of macrophages in the lungs and their changes with time after M. tuberculosis infection. This information should facilitate further investigations into both the physiology and contributions of these populations to the expression of host immunity in the lungs.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Mercedes Gonzalez-Juarrero, Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, 200 Lake Street, Fort Collins, CO 80523. E-mail address: malba{at}lamar.colostate.edu
3 Current address: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-600, South Korea.
4 Abbreviations used in this paper: BAL, bronchoalveolar lavage; FSC, forward light scatter; SSC, side light scatter; MFC, mean fluorescence channel.
Received for publication April 4, 2003. Accepted for publication July 9, 2003.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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gene-disrupted mice. J. Exp. Med. 178:2243. in resistance to Mycobacterium tuberculosis infection. J. Exp. Med. 178:2249. transcriptional responses without inhibiting activation of STAT1. J. Immunol. 163:3898. by blood monocytes from patients with active tuberculosis and presence of TGF- in tuberculosis granulomotous lung lesions. J. Immunol. 154:465.[Abstract]
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C. Jakubzick, F. Tacke, J. Llodra, N. van Rooijen, and G. J. Randolph Modulation of Dendritic Cell Trafficking to and from the Airways J. Immunol., March 15, 2006; 176(6): 3578 - 3584. [Abstract] [Full Text] [PDF]
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A. Vallon-Eberhard, L. Landsman, N. Yogev, B. Verrier, and S. Jung Transepithelial Pathogen Uptake into the Small Intestinal Lamina Propria J. Immunol., February 15, 2006; 176(4): 2465 - 2469. [Abstract] [Full Text] [PDF]
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D. Ordway, M. Henao-Tamayo, I. M. Orme, and M. Gonzalez-Juarrero Foamy Macrophages within Lung Granulomas of Mice Infected with Mycobacterium tuberculosis Express Molecules Characteristic of Dendritic Cells and Antiapoptotic Markers of the TNF Receptor-Associated Factor Family J. Immunol., September 15, 2005; 175(6): 3873 - 3881. [Abstract] [Full Text] [PDF]
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M. Sundquist and M. J. Wick TNF-{alpha}-Dependent and -Independent Maturation of Dendritic Cells and Recruited CD11cintCD11b+ Cells during Oral Salmonella Infection J. Immunol., September 1, 2005; 175(5): 3287 - 3298. [Abstract] [Full Text] [PDF]
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C. von Garnier, L. Filgueira, M. Wikstrom, M. Smith, J. A. Thomas, D. H. Strickland, P. G. Holt, and P. A. Stumbles Anatomical Location Determines the Distribution and Function of Dendritic Cells and Other APCs in the Respiratory Tract J. Immunol., August 1, 2005; 175(3): 1609 - 1618. [Abstract] [Full Text] [PDF]
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M. Srivastava, S. Jung, J. Wilhelm, L. Fink, F. Buhling, T. Welte, R. M. Bohle, W. Seeger, J. Lohmeyer, and U. A. Maus The Inflammatory versus Constitutive Trafficking of Mononuclear Phagocytes into the Alveolar Space of Mice Is Associated with Drastic Changes in Their Gene Expression Profiles J. Immunol., August 1, 2005; 175(3): 1884 - 1893. [Abstract] [Full Text] [PDF]
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J. Padilla, E. Daley, A. Chow, K. Robinson, K. Parthasarathi, A. N. J. McKenzie, T. Tschernig, V. P. Kurup, D. D. Donaldson, and G. Grunig IL-13 Regulates the Immune Response to Inhaled Antigens J. Immunol., June 15, 2005; 174(12): 8097 - 8105. [Abstract] [Full Text] [PDF]
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M. Gonzalez-Juarrero, J. M. Hattle, A. Izzo, A. P. Junqueira-Kipnis, T. S. Shim, B. C. Trapnell, A. M. Cooper, and I. M. Orme Disruption of granulocyte macrophage-colony stimulating factor production in the lungs severely affects the ability of mice to control Mycobacterium tuberculosis infection J. Leukoc. Biol., June 1, 2005; 77(6): 914 - 922. [Abstract] [Full Text] [PDF]
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L. Majlessi, P. Brodin, R. Brosch, M.-J. Rojas, H. Khun, M. Huerre, S. T. Cole, and C. Leclerc Influence of ESAT-6 Secretion System 1 (RD1) of Mycobacterium tuberculosis on the Interaction between Mycobacteria and the Host Immune System J. Immunol., March 15, 2005; 174(6): 3570 - 3579. [Abstract] [Full Text] [PDF]
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K. M. Empey, M. Hollifield, K. Schuer, F. Gigliotti, and B. A. Garvy Passive Immunization of Neonatal Mice against Pneumocystis carinii f. sp. muris Enhances Control of Infection without Stimulating Inflammation Infect. Immun., November 1, 2004; 72(11): 6211 - 6220. [Abstract] [Full Text] [PDF]
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S. L. Kraft, D. Dailey, M. Kovach, K. L. Stasiak, J. Bennett, C. T. McFarland, D. N. McMurray, A. A. Izzo, I. M. Orme, and R. J. Basaraba Magnetic Resonance Imaging of Pulmonary Lesions in Guinea Pigs Infected with Mycobacterium tuberculosis Infect. Immun., October 1, 2004; 72(10): 5963 - 5971. [Abstract] [Full Text] [PDF]
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M.-B. Voisin, D. Buzoni-Gatel, D. Bout, and F. Velge-Roussel Both Expansion of Regulatory GR1+ CD11b+ Myeloid Cells and Anergy of T Lymphocytes Participate in Hyporesponsiveness of the Lung-Associated Immune System during Acute Toxoplasmosis Infect. Immun., September 1, 2004; 72(9): 5487 - 5492. [Abstract] [Full Text] [PDF]
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W. Peters, J. G. Cyster, M. Mack, D. Schlondorff, A. J. Wolf, J. D. Ernst, and I. F. Charo CCR2-Dependent Trafficking of F4/80dim Macrophages and CD11cdim/intermediate Dendritic Cells Is Crucial for T Cell Recruitment to Lungs Infected with Mycobacterium tuberculosis J. Immunol., June 15, 2004; 172(12): 7647 - 7653. [Abstract] [Full Text] [PDF]
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K. M. Wright and J. S. Friedland Regulation of monocyte chemokine and MMP-9 secretion by proinflammatory cytokines in tuberculous osteomyelitis J. Leukoc. Biol., June 1, 2004; 75(6): 1086 - 1092. [Abstract] [Full Text] [PDF]
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S. A. Fulton, S. M. Reba, R. K. Pai, M. Pennini, M. Torres, C. V. Harding, and W. H. Boom Inhibition of Major Histocompatibility Complex II Expression and Antigen Processing in Murine Alveolar Macrophages by Mycobacterium bovis BCG and the 19-Kilodalton Mycobacterial Lipoprotein Infect. Immun., April 1, 2004; 72(4): 2101 - 2110. [Abstract] [Full Text] [PDF]
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K. Bhatt, S. P. Hickman, and P. Salgame Cutting Edge: A New Approach to Modeling Early Lung Immunity in Murine Tuberculosis J. Immunol., March 1, 2004; 172(5): 2748 - 2751. [Abstract] [Full Text] [PDF]
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A. P. Junqueira-Kipnis, J. Turner, M. Gonzalez-Juarrero, O. C. Turner, and I. M. Orme Stable T-Cell Population Expressing an Effector Cell Surface Phenotype in the Lungs of Mice Chronically Infected with Mycobacterium tuberculosis Infect. Immun., January 1, 2004; 72(1): 570 - 575. [Abstract] [Full Text] [PDF]
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