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T Cells with Activated Macrophages Is a Property of the V1 Subset 1
* School of Biochemistry and Molecular Biology, University of Leeds, Leeds, United Kingdom; and
Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
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Abstract |
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T cell function. The mechanisms by which T cells mediate this function, however, are not clear. Studies have identified a direct role for T cells in resolving the host immune response to infection, by eliminating populations of activated macrophages. The aim of this study was to identify macrophage-reactive T cells and establish the requirements/outcomes of macrophage- T cell interactions during the immune response to the intracellular bacterium, Listeria monocytogenes (Lm). Using a macrophage-T cell coculture system in which peritoneal macrophages from naive or Lm-infected TCR-/- mice were incubated with splenocytes from naive and Lm-infected 
/ T cell-deficient and wild-type mice, the ability to bind macrophages was shown to be restricted to T cells and the GV5S1 (V1) subset of T cells. Macrophage adherence resulted in a 4- to 10-fold enrichment of V1+ T cells. Enrichment of V1 T cells was dependent upon the activation status of macrophages, but independent of the activation status of T cells. V1 T cells were cytotoxic for activated macrophages with both the binding to and killing of macrophages being TCR dependent because anti-TCR Abs inhibited both V1 binding and killing activities. These studies establish the identity of macrophage cytotoxic T cells, the conditions under which this interaction occurs, and the outcome of this interaction. These findings are concordant with the involvement of V1 T cells in macrophage homeostasis during the resolution of pathogen-mediated immune responses. |
Introduction |
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A role has been identified for T cells in resolving pathogen-induced immune responses, and in contributing to macrophage homeostasis (3, 4). Accumulation of T cells has been observed in sites of inflammation associated with intracellular bacterial (e.g., Listeria monocytogenes (Lm),3 Salmonella choleraesuis) (3, 5, 6, 7), viral (e.g., influenza, Sendai virus, CMV, Coxsackieviruses) (8, 9, 10, 11), and parasitic (e.g., Toxoplasma gondii) (12, 13, 14) infections as well as in autoimmune diseases (15, 16, 17). In addition, exaggerated tissue necrosis occurs in microbe- or parasite-infected mice deficient in T cells, demonstrating a requirement for T cells in resolving pathogen-mediated immune responses and in the prevention of tissue injury (18, 19, 20, 21). Further evidence for the requirement of T cells in regulating the immune response to Lm and preventing chronic inflammation has been obtained by adoptively transferring T cells into lymphocyte-deficient, SCID mice (18). Transferred T cells abrogate the tissue injury that is usually observed in T cell-deficient mice, demonstrating that T cells are both necessary and sufficient to prevent exaggerated tissue necrosis.
This laboratory has recently identified a mechanism by which T cells prevent chronic inflammation. Using the mouse model of listeriosis, we have shown that in the absence of T cells, chronic inflammation is associated with the accumulation of large numbers of activated macrophages at the sites of infection. A population of macrophages was shown to be reactive with T cells, which subsequently acquired the ability to kill the macrophages. This is consistent with the hypothesis that T cells are directly involved in macrophage homeostasis by eliminating the activated macrophages after pathogen clearance.
A question raised by these findings is do all T cell populations possess the ability to interact with and eliminate activated macrophages, or is it restricted to a specific population? Several lines of evidence suggest that the ability to interact with macrophages may be restricted to specific subsets of T cells. After infection with Lm, T cells accumulating in sites of infection predominately express TCRs encoded by the V6 and GV5S1 (V1) gene families (22). Also, V1/V6.3 hybridomas react with and produce IFN- in response to Listeria-elicited macrophages (3).
In this study, we demonstrate that the ability to interact with Listeria-elicited activated macrophages appears to be restricted to a subset of T cells reactive with the 2.11 mAb that recognizes V1-encoded TCRs (23, 24). We have also determined the cellular activation requirements for macrophage- T cell interactions and shown that T cell binding to activated macrophages is TCR mediated.
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Materials and Methods |
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C57BL/6 wild type were purchased from Harlan Laboratories (Bicester, Oxon, U.K.). C57BL/6 TCR-/-, C57BL/6 TCR -/-, and C57BL/6 CD45.1 mice were purchased from The Jackson Laboratory (Bar Harbor, ME). All mice were housed under specific pathogen-free conditions at Leeds University and used between 6 and 8 wk of age. Mice were infected i.p. with 1.5 x 104 CFU per mouse Lm (strain 10403S) in PBS, and cells were harvested 8 days later. Thioglycolate-elicited macrophages were obtained by injecting C57BL/6 mice i.p. with 1 ml of 3% thioglycolate medium brewer modified (Sigma-Aldrich, Poole, Dorset, U.K.) in PBS, and 8 days later harvesting peritoneal exudate cells (PECs), as described below.
Abs and flow cytometry
Abs used included: F(ab')2 of Abs specific for TCR V1 (2.11; Refs. 23 and 24) TCR V6.3 (17C; 3), and TCR (GL3). The 2.11 hybridoma cell line was kindly provided by P. Pereira (Institut Pasteur, Paris, France). Commercial Abs used included: anti-mouse TCR (H57-597) and TCR (GL3), CD3 (145 2C11), B220 (RA3-6B2) conjugated to biotin, or fluorochromes purchased from Caltag-Medsystems (Towcester, U.K.) or BD PharMingen (Oxford, U.K.). Streptavidin PE, FITC (Caltag-Medsystems), or Alexa Flur 633 (Molecular Probes, Eugene, OR) were used as secondary reagents. To block nonspecific Ab binding, cells were incubated with 5% rabbit serum and mouse IgG (20 µg/ml). Isotype-matched Abs of irrelevant specificity were used to determine the level of nonspecific staining. Stained cells were analyzed on a FACSCalibur flow cytometer using CellQuest software (BD Biosciences, Oxford, U.K.).
Cell isolation
PECs were obtained by two rounds of peritoneal lavage with 5 ml of HBSS containing 10 U/ml heparin. Cells were collected by centrifugation, washed twice, and then resuspended in RPMI 1640 medium supplemented with 10% FCS. To obtain macrophages, PECs were plastic adhered by incubating cells (<5 x 106 cells/ml) for 1 h in 5% CO2 at 37°C. Splenocytes were prepared by homogenizing spleens using a glass homogenizer and passing cell suspension through a 0.7-µm nylon filter. Erythrocytes were lysed with 0.8% (w/v) ammonium chloride solution.
Macrophage and T cell coculture
Adherent PECs from C57BL/6 TCR-/- mice were cultured with splenocytes at 37°C in RPMI with 10% FCS for 1 h. In some experiments, PECs from wild-type C57BL/6 mice were used as a source of both and V1 T cells and activated macrophages. To attempt to block the interaction of T cells with macrophages, F(ab')2 of anti-V6.3 Abs were included in some experiments. Isotype-matched Abs and an anti-CD45 Ab were used as controls. Nonadherent cells were removed by gentle aspiration and washing with PBS, and macrophage-adherent cells were obtained using a cell scraper and chilled (4°C) medium. T cells were identified in the recovered cells by staining with anti-CD3, F(ab')2 of anti-TCR and anti-V1 Abs and analyzed by flow cytometry. To evaluate macrophage killing by T cells, adherent macrophages were incubated with the live/dead cell reagent (Molecular Probes) containing fluorescent dyes that identify intracellular esterase activity of viable cells (calcein AM) or are incorporated in the nucleus of dead cells (ethidium bromide homodimer-1). Slides were observed under U.V illumination using a Zeiss Axiovert 200M microscope (Welwyn Garden City, U.K.) using Axiovision image analysis software (Imaging Associates, Bicester, U.K.).
Immunohistochemistry
PECs from C57BL/6 mice were incubated on eight-well chamber slides (ICN Pharmaceuticals, Basingstoke, U.K.) at a concentration of 5 x 105 cells/well in RPMI 1640 medium and 10% FCS, for 1 h at 37°C. Nonadherent cells were removed by repeated washing with warm PBS, and the remaining adherent cells were fixed using 4% paraformaldehyde for 15 min and blocked with 0.5% (w/v) BSA, 5% rabbit serum, and 20 µg/ml mouse IgG for 10 min, before staining with biotinylated anti-V1 (2.11) and F4/80-FITC for 1 h. Cells were washed and then incubated with streptavidin Texas Red (Caltag-Medsystems) for 30 min at 20°C. Samples were then incubated for 1 min with the nuclear counterstain 4'-6-diamidino-2-phenylinodole dihydrochloride (Molecular Probes) before mounting with MOWIOL (Calbiochem, Nottingham, U.K.).
Statistics
Differences in mean values between two groups were evaluated by Mann-Whitney U tests using Statistical Package for the Social Sciences software (SPSS, Surrey, U.K.).
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Results |
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A macrophage-T cell coculture system was used to identify T cells capable of interacting with activated macrophages. Macrophage populations were obtained by plastic adherence of PECs from C57BL/6-TCR-/- mice before or after infection with Lm. Naive or Lm-infected C57BL/6 wild-type, C57BL/6-CD45.1, C57BL/6-TCR-/-, or C57BL/6-TCR-/- mice were used as sources of splenocytes and T cells for coculture with macrophages from C57BL/6-TCR-/- mice. In some experiments, macrophage populations and T cells were obtained from the same preparation of PECs from naive or treated C57BL/6 mice. Macrophage-adherent and nonadherent cells were identified by surface Ab staining and flow cytometry. This assay was also used to establish the cellular activation requirements for T cells and macrophages to interact, and whether the ability to interact with macrophages involves, or is dependent, upon the TCR.
V1 T cells bind to pathogen-elicited macrophages
The possibility that T cells might interact with macrophages was first indicated during initial attempts at isolating T cells from PECs or splenocytes of Lm-infected mice. In attempting to enrich for lymphocyte populations by plastic-adhering monocytes/macrophages, a significant number of T cells was also depleted, suggesting they might be adhering directly to plastic, or to plastic-adherent cells. By comparing the distribution and proportion of T cells in PECs in plastic-adherent and nonadherent fractions with those in the starting population before incubation with macrophages, we could determine whether there was any enrichment or depletion of specific T cell populations as a result of binding to macrophages. Our studies showed that V1+ T cells selectively bind to plastic-adherent cells (Fig. 1).
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+ V1+ cells in the plastic-adherent or nonadherent fraction with that in the starting population allowed the fold enrichment of V1+ T cells as a result of binding to plastic-adherent cells to be determined. The proportion of T cells in the adherent cell fraction increased 
4-fold (4–16% of all cells) compared with the starting population. Most striking was the difference in the populations of nonadherent vs adherent T cells. Whereas the vast majority (95%) of nonadherent T cells was V1-, virtually all (>97%) of the T cells found in the adherent fraction were V1+ (Fig. 1). There did not appear to be any obvious enrichment of other, V1-, populations in the adherent cell fraction (Fig. 1). In comparing the distribution of V1- cells in the starting population, in which they comprise 30–40% of T cells, with that in the adherent cell fraction (3%), it is unlikely that there has been any enrichment for V1- populations by adherence. By contrast, there was an increase in the proportion of V1- + cells seen in the nonadherent cell fraction (95% of all T cells) compared with the starting population (Fig. 1). The residual plastic-adherent, TCR-cells were T cells and B cells (Fig. 1 and data not shown). However, in comparing the distribution of B cells and T cells in Lm-elicited PECs before and after adherence, the majority were nonadherent, and among adherent cells there was no evidence of any enrichment for specific subsets of these lymphocytes (data not shown).
Another distinguishing feature of V1 T cells in the adherent fraction was that they expressed higher levels of CD3 compared with nonadherent V1- T cells (Fig. 1). That the enrichment of V1 T cells was a result of interactions with and binding to adherent cells and not to plastic was confirmed by the inability to detect any adherence of splenic T cells to plastic alone (data not shown).
Immunofluorescent staining of plastic-adherent Lm-elicited PECs was used to identify the adherent cells. The majority (>95%) of plastic-adherent cells were F4/80+, identifying them as macrophages. Dual Ab-labeling experiments using FITC-labeled F4/80 and Texas Red-labeled 2.11 Abs showed that V1 T cells (Fig. 2B) were found in close association with, and in some cases in direct contact with, F4/80+ macrophages (Fig. 2, D–F). Only small numbers of V1 T cells were found in isolation as single cells, and none were found in close association or direct contact with F4/80- cells (data not shown). In addition, we have also been unable to detect any binding of V1+ cells among a panel of nonhemopoietic or lymphoid cell lines (D. Newton, J. Dalton, and S. R. Carding, unpublished observations). Together these findings suggested that the interaction of the V1+ cells with other immune cells is restricted to populations of macrophages.
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1 T cell interaction with macrophages is not dependent on T cell activation, but requires prior activation of macrophages
The ability to enrich V1 T cells by macrophage adherence was dependent upon the activation status of PECs (Fig. 3). No significant level of binding or enrichment of V1 T cells was seen using PECs/macrophages from naive, noninfected animals (Fig. 3). Interestingly, activation of macrophages required for V1 T cell binding was stimulus independent because enrichment of V1 T cells was seen using macrophages elicited by sterile, noninfectious (thioglycolate), and infectious stimuli. The highest levels of V1 T cell enrichment (10-fold) were, however, seen using bacteria-elicited macrophages (Fig. 3).
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1 T cells, the ability to enrich V1 T cells by macrophage adherence was not dependent upon the activation status of T cells and elicitation by infection (Fig. 4). Using macrophages from TCR-/- mice and splenocytes from naive and Lm-infected mice as a source of (V1+) T cells, similar levels of V1 T cell enrichment (4- to 5-fold) were seen using V1 T cells from naive or Lm-infected animals.
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1 T cell enrichment (10-fold) were seen using PECs from Lm-infected wild-type mice as a source of both macrophages and (V1) T cells compared with using two different animals and tissue sources for macrophages (PECs) and T cells (splenocytes) (4- to 5-fold). This difference most likely reflects the optimal conditions and relative proportion of macrophages and T cells required to maximize V1 T cell-macrophage interactions, which is naturally present in PECs of infected wild-type mice that contain both populations of cells.
The interaction between V1 T cells and activated macrophages is TCR mediated
The ability of naive V1 T cells to bind to activated macrophages suggested that this interaction is likely to be mediated by molecules constitutively expressed by V1+ cells, and not molecules such as cell adhesion molecules, whose expression is dependent on or is modulated by activation. One such candidate molecule is the TCR. To investigate this further, we attempted to block the ability of V1 T cells to bind to Lm-elicited macrophages using F(ab')2 of the rat anti-mouse TCRV6.3 Ab, 17C (5). V1/V6.3 T cells are also the largest population of T cells normally resident in lymphoid tissues, and they are the major subset of T cells that respond to Lm infection in C57BL/6 mice (5). Analysis of macrophage-adherent T cells showed that >97% expressed the V1 and the V6.3 TCR chains (Fig. 5, A and B). Importantly, the use of the 17C Ab in these blocking experiments enabled us to use the 2.11 Ab to detect and monitor the presence and binding of V1 T cells to macrophages. As can be seen in Fig. 5C, the anti-V6.3 Ab abrogated the binding of V1 T cells to activated macrophages in a dose-dependent manner with virtually no binding seen at the highest concentrations of Abs used. By contrast, isotype-matched control Ab or an Ab to CD45 that is expressed at high levels by hemopoietic cells, including all T cells, had no significant effect on V1 T cell binding to activated macrophages. This result is consistent with our previous studies using T cell hybridomas in which macrophage reactivity was restricted to T cells expressing a V1/V6.3-encoded TCR (3). Thus, the interaction between V1 T cells and activated macrophages requires and appears to be mediated by the V1/V6.3 TCR.
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1 T cells kill activated macrophages
Although we have previously shown that Lm-elicited macrophages are killed by splenic T cells (3), the identity of macrophage cytocidal T cells was not determined. To determine whether macrophage-adherent V1 T cells possess macrophage cytocidal activity, a fluorescence-based cytotoxic (live/dead cell) assay was used to quantitate live vs dying and dead cells. This assay was first validated by determining the level of macrophage killing among T cells from wild-type mice or or T cell-deficient mice, as done previously using conventional 51Cr release CTL assays (3). As shown in Fig. 6A, activated peritoneal macrophages from Lm-infected C57BL/6-TCR-/- mice were efficiently lysed by T cells from wild-type and TCR-/- mice, but not TCR-/- mice. In the absence of T cells, the level of macrophage killing was not significantly different from that seen in cultures of macrophages conducted in the absence of T cells. This assay also demonstrates for the first time that there was no requirement for prior activation in vivo for effector T cells to acquire the ability to kill activated macrophages. Similar levels of macrophage killing were seen using T cells from naive, noninfected, and Lm-infected mice. Importantly, the level of macrophage killing detected by this fluorescent assay (40–50%) was comparable to that seen using 51Cr release assays (3).
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6.3 Ab, 17C, reduced the level of macrophage death by an average of 50% (Fig. 6B). This level of inhibition was somewhat lower than that obtained with the anti-TCR Ab, GL3 (average of 60%), in 51Cr release assays (3), which may reflect differences in the sensitivities of the assays and/or differences in the Abs used. Alternatively, it may be explained by Ab considerations such as accessibility, affinity, or amounts used, or that other minor populations of macrophage-adherent (V1/V6.3-) T cells kill activated macrophages. By contrast, control Abs, including an Ab to CD45, which is expressed at high levels by T cells and binds independently of the TCR, had no significant effect on macrophage killing. These findings are consistent with V1 T cells being able to kill activated macrophages as a result of TCR-mediated interactions. |
Discussion |
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T cells and macrophages in mice infected with the intracellular bacteria, Lm (3), in which T cells are stimulated by macrophages to acquire macrophage cytocidal activity. This current study both confirms these findings and extends them by identifying the T cell population that accounts for this activity. This study has also identified a requirement of the TCR for macrophage recognition and binding, and the cellular activation requirements for T cell-macrophage interactions. Macrophage reactivity has been shown to reside within the V1/V6.3 subset of T cells, which acquire the ability to kill activated macrophages. It is interesting to note that a similar T cell-macrophage interaction has been identified in humans in which monocytic cell lines (25) or bacteria-infected monocytes (26) were shown to serve as APCs for V9/V2 T cells. We believe that this is the first study to establish the identity of the (target) cells that the murine V1 population of T cells interacts with during an immune response. Macrophage cytotoxicity activity is an inherent property of V1 T cells, is independent of their activation status, and is TCR mediated. By contrast, V1-reactive macrophages reside within a population of activated macrophages that are absent in naive animals, but are generated in response to both infectious and noninfectious stimuli. This requirement for macrophage activation to interact with and to bind V1 T cells might function as a self-defense mechanism to normally protect the macrophages in healthy, noninfected animals from cytotoxic V1 T cells. These results are consistent with the hypothesis that T cells, specifically V1 T cells, are involved in maintaining macrophage homeostasis during pathogen-induced immune responses by down-regulating activated macrophages after pathogen clearance.
V1 T cells have been shown to dominate the T cell response during the immune response to a variety of pathogens, including Lm (5), S. choleraesuis (27), influenza virus (8), Sendai virus (9), CMV (10), and Coxsackievirus B3 (28) in specific strains of mice. It is possible that the V1 T cell response to each of these pathogens is distinct and involves different subsets of V1 T cells with different Ag specificities. Indeed, structural analyses of TCRs expressed by V1/V6.3+ T cells have shown that they are structurally diverse TCRs (24, 29, 30, 31) with the potential therefore to recognize large numbers of different Ags. It is worth noting, however, that to date no Ag- or pathogen-specific V1 T cells have been identified.
Although we have not attempted to identify the molecular nature of the stimulating ligand(s) expressed by activated macrophages, it could be of pathogen and/or endogenous origin. One such candidate molecule is heat shock protein 60 (hsp60). V1/V6 T cell hybridomas are able to recognize hsp60 of both bacteria and mammalian origin (32). Of note, as a consequence of infection, populations of activated macrophages express plasma membrane-associated hsp60 (5). Additional experiments are needed to determine whether hsp60 is the ligand that facilitates the interaction of V1 T cells with activated macrophages.
The results of our study provide an explanation for the apparent dominance of V1 T cells in pathogen-mediated immune responses. The absence of any apparent specificity in the stimuli required to elicit V1-reactive macrophages, and the fact that macrophage binding is a property of virtually all splenic V1 T cells in the naive as well as Lm-infected C57BL/6 mouse strongly suggest that the V1 T cell response is invoked by populations of macrophages that are elicited and activated in response to a variety of inflammatory stimuli. Although our studies clearly identify macrophages as being the cellular mediators of the V1 T cell response to Listeria infection, it remains to be determined whether this cell-cell interaction accounts for the involvement of V1 T cells in the immune response to other pathogens.
Our findings demonstrate that macrophage cytotoxicity is an important functional attribute of V1/V6.3 T cells. What our study has been unable to address, however, is how homogenous V1/V6.3 T cells are and whether they all possess the ability to kill activated macrophages, or whether they have other functional capabilities in addition to, or instead of, cytotoxicity. Our studies using the murine listeriosis model suggest that this population of T cells is functionally diverse and may change during the course of an immune response (4, 5). The V1 T cell response to Lm infection in C57BL/6 mice is biphasic and peaks in number during both the early and late phases of the immune response, with each having different effector function profiles. Late responding V1 T cells are defined by macrophage cytotoxicity and production of anti-inflammatory cytokines, whereas early responding V1 T cells produce proinflammatory cytokines (3) (unpublished observations). What is not clear at this time is whether these different functional properties are expressed by the same or different subsets of V1 T cells, whether the effector function of V1 T cells is fixed or can change according to the conditions of activation, and what the significance of these different functional properties is to the development of protective immunity.
A clue to the possible significance and importance of cytokine production by V1 T cells has been obtained by Huber and colleagues using the mouse model of Coxsackievirus B3-induced myocarditis. By adoptively transferring V1+ cells from mice defective in the production of either IFN- (STAT4-/- mice) or IL-4 (STAT6-/- mice) to virus-infected wild-type mice, IL-4+ V1 cells, but not IFN-+ cells were shown to suppress myocarditis, implying that cytokines made by V1 T cells are important in modulating CD4 Th cell responses and myocarditis susceptibility (33, 34). This is not entirely inconsistent with our proposal that the primary function of V1 T cells is to influence macrophage function and fate (3). The effects of V1 T cells on CD4 Th phenotype seen in Coxsackievirus infection might also be explained by V1-derived cytokines acting on macrophages that subsequently alter Th cell generation.
The importance of (macrophage cytocidal) V1 T cells for the outcome of Lm infection is uncertain. The removal and elimination of activated macrophages after pathogen clearance are considered to be important in preventing chronic inflammation and promoting tissue repair, and V1 T cells can contribute to this process in Listeria-infected mice (3). There are reports, however, suggesting that V1 T cells can have both beneficial and detrimental effects. In two different studies, Ab-mediated depletion of V1 T cells has been shown to either increase (35) or decrease (36) bacterial burden. Because the conditions of infection (dose and route) influence both the timing and magnitude of the V1 T cell response to Lm infection (5), these opposing results may reflect differences in bacterial virulence, the use of the different infectious doses and routes of infection, and times of analysis postinfection used in the two studies.
In summary, our studies have identified an interaction between T cells and activated macrophages that appears to be restricted to the V1 population consistent with their role in maintaining macrophage homeostasis during the immune response to infection.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Simon R. Carding, School of Biochemistry and Molecular Biology, University of Leeds, Leeds, LS2 9JT, U.K. E-mail address: S.R.Carding{at}Leeds.ac.uk
3 Abbreviations used in this paper: Lm, Listeria monocytogenes; PEC, peritoneal exudate cell; hsp, heat shock protein.
Received for publication July 9, 2003. Accepted for publication October 3, 2003.
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T cell subset can increase host resistance to a bacterial infection. J. Immunol. 165:6472.This article has been cited by other articles:
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), rat IgG2b (
), or anti-CD45 (
) Abs. The percentage binding of V
), or C57BL/6-TCR