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The Journal of Immunology, 2003, 170: 5345-5348.
Copyright © 2003 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Major CD8 T Cell Response to Live Bacillus Calmette-Guérin Is Mediated by CD1 Molecules1

Tetsuo Kawashima*,{dagger}, Yoshihiko Norose*, Yoshiyuki Watanabe*,{dagger}, Yutaka Enomoto*,{dagger}, Hidehiko Narazaki*, Eiji Watari*, Shigeo Tanaka{dagger}, Hidemi Takahashi*, Ikuya Yano{ddagger}, Michael B. Brenner§ and Masahiko Sugita2,*

* Department of Microbiology and Immunology and {dagger} Second Department of Surgery, Nippon Medical School, Tokyo, Japan; {ddagger} Japan BCG Laboratory, Kiyose, Tokyo, Japan; and § Lymphocyte Biology Section, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
MHC class I-restricted CD8+ T cells are a crucial component of the host defense against mycobacterial infection in mice, but it has often proved very difficult to identify the CD8 T cell response in humans. Human group 1 CD1 molecules (CD1a, -b, -c) mediate MHC-independent presentation of mycobacteria-derived lipid and glycolipid Ags to CD8+ T cells, and their intracellular localization to the endocytic system may favor efficient monitoring of phagosome-resident mycobacteria. Here, we show that bacillus Calmette-Guérin (BCG)-immunized subjects contain a significant circulating pool of CD8+ T cells that recognize BCG-infected DCs in a CD1-dependent, but MHC-independent, manner. These CD1-restricted T cells efficiently detected live, rather than dead, BCG and produced IFN-{gamma}, an important cytokine for protection against mycobacterial infection. These results emphasize that lipid-reactive CD8+ T cells may contribute to host defense against mycobacterial infection.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Besides the prominent role of CD4+ T cells and IFN-{gamma} that they produce in host defense against mycobacterial infection, CD8+ T cells appear to mediate distinct but complementary pathways for controlling intracellular mycobacteria (1, 2). Evidence obtained from analysis of TAP- and CD1d-deficient mice as well as an earlier study of mice lacking the expression of {beta}2-microglobulin unequivocally demonstrated a significant contribution of MHC class I-restricted CD8+ CTLs in clearing mycobacterial infection in mice (3, 4). In humans, the potential role of CD8+ T cells in protection against mycobacterial infection has been appreciated partially by isolating and characterizing mycobacteria-specific, MHC class I-restricted CD8+ T cell lines (5). These studies focused on macrophages, the well-known reservoir for mycobacteria, as CTL target cells, that were either infected with mycobacteria or pulsed with mycobacteria-derived peptide Ags.

Recently, the universe of human CD8+ CTLs has been expanded to include those that recognize mycobacterial cell wall-derived lipid and glycolipid Ags in the context of group 1 CD1 molecules (CD1a, -b, and -c) expressed prominently and almost exclusively on dendritic cells (DCs)3 (6). Given that DCs are the most efficient APCs in the immune system and that, besides macrophages, DCs represent another important reservoir for mycobacteria (7), group 1 CD1-dependent activation of CD8+ T cells may occur during the course of mycobacterial infection (8). In addition, CD1 molecules are expressed intracellularly in endocytic subcompartments where lipid Ags derived from phagocytosed mycobacteria are known to traffic (9, 10), raising the possibility that CD1 molecules may be situated to efficiently monitor infection with live mycobacteria. Indeed, group 1 CD1-restricted CD8+ T cell lines were isolated from healthy subjects as well as patients with mycobacterial infection, and their outstanding ability to recognize mycobacteria-infected cells and kill the intracellular organisms has been noted (11). Thus, despite the previous observations that a majority of human circulating CD8+ T cells may recognize mycobacteria-infected cells in a CD1-independent manner (12, 13), we reasoned that a circulating pool of CD1-restricted CD8+ T cells reactive to live mycobacteria might be detected in those who have established augmented cell-mediated immunity against mycobacterial infection. In the present study, we show that a sizable pool of such CD8+ T cells exists in the peripheral blood of individuals inoculated with live Mycobacterium bovis bacillus Calmette-Guérin (BCG) and that these CD1-restricted T cells produce IFN-{gamma} in response to live BCG-infected DCs. Lipid Ag-reactive CD8+ T cells may therefore contribute to host defense against mycobacterial infection.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
BCG culture and infection

The Tokyo 172 strain of BCG was grown in 7H9 medium and the extraction with chloroform/methanol was performed as described previously (14). TLC of the organic extract was conducted on 200-µm silica-coated glass TLC plates developed in 50% sulfuric acid as described (14). For infection experiments, BCG was harvested at its midlog phase growth, washed, and suspended in RPMI 1640 (Life Technologies, Gaithersburg, MD) supplemented with 10% FCS (HyClone Laboratories, Logan, UT). Without prior sonication, the suspension was passed through a 5-µm pore size filter to obtain single-cell bacteria. The viability of bacteria was constantly >90%. The BCG preparation was divided into equal aliquots; one aliquot was incubated for 30 min at 85°C to kill the bacteria, whereas the other aliquot was left at room temperature. Human peripheral blood monocytes and monocyte-derived DCs were isolated as described (15) and incubated for 4 h with the BCG preparations at the multiplicity of infection of 10. The infected cells were then washed and incubated for an additional 14 h in RPMI 1640 complete medium without antibiotics. At the end of the culture, the cells were harvested, irradiated, and used as APCs in T cell stimulation assays and ELISPOT assays.

T cell transfectants stimulation assays

Reconstitution of the LDN5 TCR in TCR-deficient Jurkat cells (J.RT3/LDN5) was conducted as described (14). The J.RT3/LDN5 cells (5 x 104/well) were cultured for 20 h with either BCG-infected, glucose monomycolate (GMM)-pulsed, or untreated DCs (5 x 104/well), and the amount of IL-2 released into the supernatants was measured as described (14).

ELISPOT assays

PBLs were obtained from 11 healthy Japanese subjects (donors 1–11) who had positive purified protein derivative (PPD) test conversion due to BCG vaccine inoculation at their infancy. The subjects included 8 men (donor 1, 30 years old; donor 3, 32 years old; donor 5, 30 years old; donor 6, 32 years old; donor 7, 34 years old; donor 8, 33 years old; donor 9, 30 years old; donor 10, 44 years old) and 3 women (donor 2, 32 years old; donor 4, 33 years old; donor 11, 33 years old). After incubation of the PBLs at 4°C in the presence of anti-CD19 and anti-CD56 Abs (both from BD PharMingen, San Diego, CA) together with Abs against either CD4 (OKT4) or CD8{alpha} (OKT8) (15), the labeled cell populations were removed by two cycles of separation with magnetic beads coated with goat anti-mouse IgG Abs. The efficiency in depletion of the corresponding T cell populations was determined by flow cytometry as described (14). The CD8 T cell-enriched and the CD4 T cell-enriched populations (1 x 105/well) were separately incubated for 24 h with APCs (1 x 104/well), and ELISPOT assays were performed as described (5). In some experiments, the culture was performed in the presence of saturating amounts of either W6/32 (anti-MHC class I) (16, 17), L243 (anti-HLA-DR) (18), 10H3.9.3 (anti-CD1a) (14), BCD1b3.1 (anti-CD1b) (14), F10/21A3.1 (anti-CD1c) (14), or RPC5.4 (control; obtained from the American Tissue Culture Collection, Manassas, VA). Each experiment was repeated two to four times to confirm reproducibility of the results.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
A CD1b-restricted T cell line recognized DCs infected with live BCG

To evaluate the ability of CD1 to monitor mycobacterial infection, we first used a CD1-restricted T cell line, LDN5 (19), that was specific for GMM produced by several species of mycobacteria. Indeed, BCG grown for 7 days in 7H9 medium supplemented with 3% D-glucose produced a significant amount of GMM in culture (Fig. 1A, arrowhead). To examine GMM recognition in BCG-infected CD1+ cells, monocyte-derived DCs were infected with either live or heat-killed BCG and used as APCs. For detection of GMM presentation by these DCs, TCR-deficient Jurkat cells (J.RT3) reconstituted by transfection with the LDN5 TCR {alpha}- and {beta}-chains (J.RT3/LDN5) (14) were used as responder cells that were capable of recognizing GMM in the context of CD1b molecules. As expected, GMM-pulsed DCs, but not unpulsed cells, were able to stimulate the J.RT3/LDN5 cells to produce IL-2 (Fig. 1B, DC + GMM and untreated DC, respectively). DCs infected with live BCG were efficiently recognized by J.RT3/LDN5 cells, indicating that GMM was presented by live BCG-infected DCs (Fig. 1B, DC + live BCG). Despite the fact that phagocytosis of live and dead BCG occurred in similar efficiency and the bacilli contained a significant amount of GMM in their cell wall (Fig. 1A), DCs treated with dead BCG were incapable of or markedly inefficient in stimulating J.RT3/LDN5 cells. The level of IL-2 produced by J.RT3/LDN5 in response to dead BCG-infected DCs was similar to that produced in the presence of untreated DCs (Fig. 1B, DC + dead BCG and untreated DC, respectively). Purified GMM that was heat treated was presented to J.RT3/LDN5 cells as efficiently as non-heat-treated GMM (data not shown), ruling out the possibility that heat-killed BCG might contain denatured GMM. These observations suggested that CD1b molecules functioned efficiently in monitoring live mycobacterial infection but that they might not present all Ags equally well from dead bacteria.



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  		FIGURE 1. Activation of J.RT3/LDN5 cells by DCs infected with live BCG. A, The BCG organic extract as well as purified trehalose 6,6'-dimycolate (TDM) and GMM were resolved on silica TLC plates. Left, Spots corresponding to each glycolipid. B, J.RT3/LDN5 T cells were incubated with DCs that were untreated, GMM pulsed, or treated with either dead or live BCG for 20 h, and the amount of IL-2 released into the supernatants was measured.

 
A pool of peripheral blood CD8+ T cells recognized live BCG in a CD1- rather than MHC-dependent manner

The importance of CD8+ CTLs in efficient host defense against mycobacterial infection has been well noted in mice (3, 4). Yet, it has proved difficult to identify the CD8 T cell response in humans. Thus, we sought to compare CD1-restricted and MHC-restricted responses of T cells in human peripheral blood. We used BCG-immunized subjects and examined the ability of the peripheral blood T cells to recognize live BCG-infected APCs. Given that group 1 CD1-restricted T cells have often been detected in CD4-negative T cell populations and are capable of producing IFN-{gamma} on antigenic stimulation (11, 20), we prepared CD8+ T cell-enriched and CD4+ T cell-enriched populations by negative selection with appropriate Abs and magnetic beads (Fig. 2A, left and right, respectively) before performing IFN-{gamma} ELISPOT assays. As shown in Fig. 2B, these two T cell populations were separately analyzed in triplicate in ELISPOT assays in the presence of autologous DCs that were uninfected or infected with either dead or live BCG (DC + dead BCG and DC + live BCG, respectively), and spots representing IFN-{gamma}-producing cells were visualized (Fig. 2B, top) and counted (Fig. 2B, bottom). Whereas only a small number of CD8+ T cells showed reactivity to DCs infected with dead BCG, a much larger pool was detected for live BCG-reactive CD8+T cells (Fig. 2B, left). For comparison, the CD4+ T cell population from the same subject was also analyzed for its reactivity to dead and live BCG (Fig. 2B, right). In contrast to the CD8+T cell population that preferentially recognized live BCG, the CD4+ T cell population responded better to dead BCG than to live BCG.



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  		FIGURE 2. Detection of a circulating pool of live BCG-reactive CD8+ T cells. A, The CD8 T cell-enriched (left) and the CD4 T cell-enriched (right) populations were isolated from donor 1 by negative selection, labeled with anti-CD8 and anti-CD4 Abs, respectively, and analyzed by flow cytometry (filled area). Open area, negative control staining. B, ELISPOT assays were performed in triplicate, using CD8+ T cells and CD4+ T cells as responder cells and autologous DCs that were uninfected or infected with either dead or live BCG as APCs. Spots representing IFN-{gamma}-producing cells were visualized (upper panels). The spots were counted, and the mean values plus SD are shown (lower panels). C, Similar ELISPOT assays were performed, using autologous monocytes (Mo). Specific CD8+ T cell activation occurred in the presence of live BCG-infected DCs, but not monocytes.

 
Besides DCs, macrophages are a well-known reservoir for mycobacteria (7). Unlike DCs that express both MHC and CD1 molecules, macrophages express MHC molecules prominently but lack the expression of group 1 CD1 molecules, and thus often serve as convenient APCs to analyze MHC-dependent Ag presentation pathways separately from those mediated by CD1. Therefore, we tested whether the specific CD8+ T cell response to live BCG observed above with DCs might also be detected in the presence of autologous monocyte-derived macrophages. Strikingly, these CD1-negative APCs failed to activate BCG-specific CD8+ T cells (Fig. 2C, left) but were capable of stimulating specific CD4+ T cells, albeit less prominently than DCs (Fig. 2C, right). Thus, it seemed likely that the BCG-specific CD8+ and the CD4+ T cell responses might be differentially mediated by CD1 and MHC class II molecules, respectively.

To clearly determine restriction elements that were involved in live BCG recognition by these two T cell populations, ELISPOT assays with live BCG-infected DCs were performed in the presence of blocking Abs against MHC and CD1 molecules, and the percent inhibition for each Ab was calculated. Whereas the CD4+T cell response to live BCG was blocked solely by anti-MHC class II Ab (Fig. 3A, right), the CD8+ T cell response to live BCG was blocked most significantly by anti-CD1b Ab and moderately by anti-CD1a and anti-CD1c Abs, but not by Abs to MHC molecules (Fig. 3A, left) and anti-CD1d Abs (data not shown). Significant blockade of the CD8+ T cell response to live BCG with anti-CD1 Abs (p < 0.05 in F test), but not by anti-MHC Abs, was observed in all 11 individuals thus far examined (Fig. 3B). Thus, these studies detect a circulating pool of CD1-restricted CD8+ T cells that potentially monitor live mycobacterial infection.



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  		FIGURE 3. CD1-dependent recognition of live BCG by CD8+ T cells. A, IFN-{gamma} ELISPOT was performed in the presence of indicated blocking Abs, using T cells from donor 1 as responders and live BCG-infected autologous DCs as APCs. Blocking effect of each Ab was expressed as percent inhibition for the CD8+ (left) and the CD4+ (right) T cell populations. The mean numbers of positive spots for CD8+ and CD4+ T cells before Ab inhibition were 32 and 28, respectively. B, Similar Ab blocking analysis in ELISPOT assays was performed for CD8+ T cells obtained from 10 different donors (donors 2–11) in the presence of live BCG-infected autologous DCs, and the blocking effect of each Ab was expressed as percent inhibition. The mean numbers of positive spots before Ab inhibition were 40.6, 24.6, 71.3, 13, 22, 24.6, 10.3, 21, 49.6, and 15 (from donors 2 through 11).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Live mycobacteria exhibit an outstanding ability to survive and replicate in phagosomes by inhibiting phagosomal acidification and phagosome-lysosome fusion. MHC class I and II molecules function inefficiently in mycobacteria-infected cells, because mycobacteria evasion mechanisms render protein Ags produced in phagosomes unlikely to gain easy access to the cytosol for MHC class I presentation and the lysosome for MHC class II presentation (21). In contrast, lipid and glycolipid Ags released from phagocytosed mycobacteria are often inserted into the phagosomal membrane and then traffic out of the phagosome (22). These lipids travel throughout the endocytic system of the host cell, including early recycling endosomes and lysosomes, where CD1a and CD1b molecules traffic, respectively (9). Further, CD1c molecules are expressed broadly throughout the endocytic system (10). Thus, the intracellular trafficking of phagosome-derived lipid Ags in live mycobacteria-infected cells correlates with the endocytic distribution of CD1 molecules, enabling monitoring of live mycobacterial infection by the CD1 system.

In contrast, the intracellular delivery of phagocytosed dead mycobacteria is different from that for live mycobacteria, resulting in distinct pathways for Ag processing and presentation. Phagocytosed dead mycobacteria reside in phagosomes only transiently and are quickly delivered to the acidic, proteolytically active lysosomal compartments, where MHC class II molecules readily bind processed peptide Ags. The cell wall structure of dead mycobacteria that contains CD1-restricted lipid Ags also reaches the lysosome where CD1b and CD1c molecules are expressed; yet the rigid cell wall packed densely with extremely hydrophobic lipid molecules that are either covalently or noncovalently attached to each other and to the underlying arabinogalactan and peptidoglycan multilayers is hard to digest to release individual lipid components in a form that is readily sampled by CD1 molecules. Thus, the intracellular availability and distinct pathways for lipid and protein Ag processing and trafficking are likely to account for differential recognition of live and dead mycobacteria by CD1 and MHC class II molecules.

In contrast to the results presented here, previous studies have failed to detect mycobacteria-specific, CD1-restricted CD8+ T cells in the peripheral blood of PPD+ individuals (12, 13). These individuals may have had positive PPD test conversion due to natural infection with certain mycobacteria species, whereas the individuals analyzed in the present study had positive skin test conversion due to percutaneous BCG vaccine inoculation. Because alveolar mucosa and skin contain distinct subsets of macrophages and DCs, differences in the route of infection may significantly affect the quality and magnitude of T cell responses induced.

Most mycobacterial lipid-specific, CD1-restricted T cell lines thus far established are CD4-, and their potential ability to control mycobacterial infection has been demonstrated in vitro, especially for CD8+ T cells that produce granulysin, a bactericidal protein that directly kills mycobacteria (23). These CD1-restricted T cells notably show broad reactivity to a variety of mycobacteria species (19), contrasting MHC-restricted T cells that are highly specific and often lose reactivity when single amino acid mutation is introduced into the specific peptide Ag. Further, recent evidence has suggested that CD1-dependent lipid Ag presentation may play a crucial role in the early stages of host defense by interacting with immature DCs, even before peptide Ag-specific T cells are activated and fully expand (15, 24). Thus, the ability of CD1 to monitor infection with a broad spectrum of live mycobacteria may provide the immune system with an efficient way for the early defense against invading mycobacteria. The detection of a significant circulating pool of live mycobacteria-reactive, CD1-restricted T cells in previously infected donors emphasizes the possibility that lipid reactive T cells may contribute to host defense against mycobacterial infection.


   Acknowledgments
 
We thank Drs. D. B. Moody, D. Olive, and C. Mawas for their gifts of reagents.


   Footnotes
 
1 This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology (Grant-in-aid for Scientific Research on Priority Areas) and from Kampou Science Foundation (to M.S.). Back

2 Address correspondence and reprint requests to Dr. Masahiko Sugita, Department of Microbiology and Immunology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan. E-mail address: msugita{at}nms.ac.jp Back

3 Abbreviations used in this paper: DC, dendritic cell; BCG, bacillus Calmette-Guérin; GMM, glucose monomycolate; PPD, purified protein derivative. Back

Received for publication December 5, 2002. Accepted for publication March 27, 2003.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
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M. Gilleron, S. Stenger, Z. Mazorra, F. Wittke, S. Mariotti, G. Bohmer, J. Prandi, L. Mori, G. Puzo, and G. De Libero
Diacylated Sulfoglycolipids Are Novel Mycobacterial Antigens Stimulating CD1-restricted T Cells during Infection with Mycobacterium tuberculosis
J. Exp. Med., March 1, 2004; 199(5): 649 - 659.
[Abstract] [Full Text] [PDF]

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