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Centro de Pesquisas Gonçalo Moniz, FIOCRUZ, Rua Waldemar Falcão, 121, Salvador, Bahia 40296-710, Brazil,1 Faculdade de Medicina, UFBA, Praça XV de Novembro, S/N, Largo do Terreiro de Jesus Salvador, Bahia 40025-010, Brazil,2 Núcleo de Medicina Tropical, UFC, Rua Alexandre Baraúna, 949, Fortaleza, Ceara 60430-160, Brazil,3 Departamento de Biointeração, ICS, UFBA, Av. Reitor Miguel Calmon, S/N, Salvador, Buenos Aires 40110-160, Brazil,4 Instituto de Investigação em Imunologia, São Paulo, Brazil5
Received 17 February 2006/ Returned for modification 17 March 2006/ Accepted 16 May 2006
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ABSTRACT |
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INTRODUCTION |
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Anti-Leishmania cell-mediated immunity (CMI) is present in the majority of CL patients, as evidenced by a positive delayed-type hypersensitivity (DTH) reaction, as well as by gamma interferon (IFN-
) production by peripheral blood mononuclear cells (PBMCs) after in vitro restimulation with soluble Leishmania antigen (SLA). PBMCs of individuals vaccinated with Leishmania antigen produce IFN- and undergo CD8+ T-cell expansion upon antigen stimulation in vitro (20, 30). Moreover, we have shown that in vitro priming responses can be used to predict the pace of IFN- production in individuals vaccinated with Leishmania (41). Evaluation of CMI in human leishmaniasis has focused mainly on cytokine production, and few studies have been performed to characterize the antigenic specificity or the functionality of T-cell populations. In an experimental model of CL, expansion of V
8- and Vß4-expressing T cells has been related to susceptibility in mice infected with Leishmania major ( 36, 43, 44).
T cells recognize foreign antigens through T-cell antigen receptors (TCRs), and diversity in antigen recognition is generated by and ß genes that rearrange randomly in differentiating T cells. In this sense, the study of the TCR repertoire may contribute to the understanding of disease pathogenesis and, for this reason, has been an important focus of research in several diseases (16, 22, 31, 35, 37, 38, 53). Either PCR-based methods (14, 46, 47) or flow cytometry using TCR Vß-specific monoclonal antibodies (5, 8, 15, 27) has been employed to analyze the expression of TCR and ß variable genes. Moreover, studies of the TCR Vß repertoire have also described the role played by microbial toxins or superantigens in activating the human immune system (9, 12, 27, 29). Superantigen stimulation of the immune system or stimulation by dominant antigens leads to the proliferation of specific T-cell populations followed by clonal deletion (18, 52).
Regarding human leishmaniasis, it is known that T cells play an important role in mediating CMI against the parasite, and it has been shown that the predominant T cell in CL lesions bears the ß TCR (33, 34, 40). The TCR Vß repertoire present in CL patients' lesions caused by Leishmania braziliensis was skewed compared to the repertoire detected in the blood (51). It was found that specific T-cell populations localized to CL lesions, and Vß families 3, 6.6/6.7, and 7 were predominant in the lesions of 50% of patients studied. Since T cells are also involved in the pathogenesis of cutaneous leishmaniasis, it remains important to understand how infection leads to the expansion of the TCR Vß repertoire and, particularly, which Leishmania antigens lead to this expansion. In the present work, we evaluated the TCR Vß repertoire in CL patients, and we have compared these findings with those obtained following vaccination of healthy individuals and following in vitro priming with Leishmania parasites. Our aim was to investigate how T cells bearing the different Vß families respond in such different settings.
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MATERIALS AND METHODS |
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Isolation of PBMCs. PBMCs from CL patients, controls from the area of L. braziliensis endemicity, and vaccinated volunteers were obtained by passage over a Ficoll-Hypaque gradient (Sigma). PBMCs were stained directly for ex vivo evaluation of TCR Vß, CD4, and CD8 expression by flow cytometry or were used for in vitro priming.
Parasite and antigen. L. amazonensis MHOM/BR/87/BA125 was used for in vitro priming and antigen preparation. Details concerning isolation and characterization of this parasite strain have been described elsewhere (1). Parasites were cultivated in Schneider's medium (Sigma) supplemented with 5% fetal calf serum and gentamicin (50 µg/ml) (both from Invitrogen). In vitro stimulation of PBMCs was performed with stationary-phase promastigotes. SLA was prepared as described previously (42).
Lymph node aspiration and cell culture. Lymph nodes from CL patients were aspirated using a 19-gauge needle on a 10-ml syringe as described previously (2). Cells obtained by lymph node aspiration were stained directly for ex vivo evaluation of TCR Vß, CD4, and CD8 expression by flow cytometry or washed three times and resuspended at a concentration of 3 x 106/ml in RPMI 1640 medium supplemented with 2 mM L-glutamine, penicillin (100 U/ml), streptomycin (100 µg/ml) (all from Invitrogen), and 10% human AB serum (Sigma). Cells were plated in 48-well plates (Costar) and incubated at 37°C in 5% CO2 in the presence or absence of SLA (4 µg/ml) for 5 days. Cells were then collected and stained for evaluation of TCR Vß, CD4, and CD8 expression by flow cytometry.
In vitro priming with Leishmania. In vitro priming was performed as described previously (7), with modifications. PBMCs were obtained as described above, and cells were washed and resuspended in supplemented RPMI 1640 medium at a concentration of 5 x 106 cells/ml. From this suspension, a total of 107 cells was used for the first stimulation. The remaining cells were plated in 24-well plates, and after 30 min, nonadherent cells were removed. Adherent cells were washed and cultivated in complete medium for 5 days to allow maturation into macrophages. These macrophages were used as antigen-presenting cells in the second round of stimulation. For the first stimulation, PBMCs (5 x 106 cells/ml) were cultivated in the presence or absence of L. amazonensis promastigotes (MHOM/BR/87/BA125) at 37°C in 5% CO2 for 6 days. On day 5, mature macrophages were infected with live L. amazonensis promastigotes at a ratio of 10:1 for 24 h at 37°C in 5% CO2. Cells recovered from the first stimulation were boosted (1 x 106 cells/ml) with the autologous Leishmania-infected mature macrophages in complete RPMI 1640 medium, supplemented with 10% supernatant harvested from the first stimulation, and were cultured for 4 days. Cells were then collected and stained for evaluation of TCR Vß, CD25, CD4, and CD8 expression by flow cytometry.
Flow cytometry. Cells were stained, simultaneously, with antihuman surface CD4 (RPA-T4) and CD8 (RPA-T8) conjugated to phycoerythrin and peridinin chlorophyll protein, respectively (both from BD Biosciences), and anti-TCR Vß2 (E22E7-2), Vß3 (LE-89), Vß5 (ER-2), Vß6.1 (CR1034-3), Vß8 (6C5), Vß11(C21), Vß12 (VER2-32), Vß13 (JU-72), Vß14 (CAL-1.3), Vß16 (TAMA-1), Vß17 (E17.5), Vß20 (ELL-14), Vß21.3 (IG-125), and Vß22 (IMM-546) conjugated to fluorescein isothiocyanate (all from Immunotech). In some cases, cells were stained, simultaneously, with antihuman surface CD4 (RPA-T4) or CD8 (RPA-T8), antihuman interleukin-2R (IL-2R) conjugated to phycoerythrin (FTR-D4) (BD Biosciences), and TCR Vß12 (VER2-32). Isotype controls were used as appropriate. For each sample, 20,000 events were analyzed using CELLQuest software and a FACSort flow cytometer (Becton Dickinson Immunocytometry).
Statistical analysis. Comparison of levels of TCR Vß expression among CL patients as well as among controls was performed using the Kruskal-Wallis test, and comparison of TCR Vß expression levels in the same individuals was performed using the Wilcoxon matched-pair test. Statistical analyses were performed using GraphPad for Windows (Prism Software).
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RESULTS |
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production following in vivo immunization.
We have previously shown that healthy individuals can be categorized as either high IFN- producers (high cytokine production by PBMCs) or low IFN- producers (low cytokine production by PBMCs) upon in vitro priming of PBMCs with live Leishmania parasites (41). In the previous experiments, we observed a consistent modulation in the expression of TCR Vß12. In fact, among all the Vß TCRs tested, TCR Vß12 was the only one for which a significant increase or decrease in expression was detected in all the settings tested. Therefore, taking into account our previous data on the amount of IFN- produced by healthy volunteers and the participation of TCR Vß12 that we had observed so far, we probed for a possible association between TCR Vß12 expression and IFN- production in vaccinated individuals. In order to do so, we assayed IFN- production before and after vaccination, and at these same time points, we evaluated TCR Vß12 expression in PBMCs. Table 1 shows the IFN- production for eight vaccinated individuals. Before immunization, IFN- production following antigen stimulation was above 300 pg/ml, except in two volunteers (volunteers 1 and 6), who were therefore termed "low" producers. As shown in Fig. 5, TCR Vß12 expression before vaccination was low, both for CD4+ (Fig. 5A) and CD8+ (Fig. 5B) T cells, for all eight individuals tested. Sixty days postvaccination, we observed that IFN- production was above 1,000 pg/ml except in volunteers 1 and 6 (Table 1). When we looked at TCR Vß12 expression at this same time (Fig. 5), we observed that it increased after vaccination, and this increase was particularly evident in the six individuals for whom IFN- production was high (>1,000 pg/ml). This can be observed for both TCR Vß12 CD4+ (Fig. 5A) and TCR Vß12 CD8+ (Fig. 5B) cells. Therefore, an association between IFN- production and TCR Vß12 expression exists, and it was not found for other TCRs tested (Vß13, Vß14, and Vß16) (data not shown).
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production, we then examined whether Vß12 expression was also associated with cell activation as measured by IL-2R (CD25) expression. In order to do so, we selected 10 healthy individuals previously categorized as high IFN- producers and performed in vitro priming of their cells with live Leishmania parasites, as described above. Cells were then stained for the expression of either TCR Vß12 alone or both TCR Vß12 and IL-2R (CD25). As seen in Fig. 6A, in vitro priming with parasites leads to a significant increase in the expression of both TCR Vß12 and IL-2R in CD4+ T cells compared to that in unprimed cells. This same effect was also observed in CD8+ T cells (Fig. 6B), indicating that TCR Vß12-bearing cells expand and are activated in the presence of L. amazonensis. We performed this same experiment for the analysis of TCR Vß2 and TCR Vß5 expression, and no statistically significant differences were observed among cells primed or not primed with L. amazonensis parasites (data not shown).
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DISCUSSION |
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We began our study by examining the TCR Vß repertoire in CL patients from an area in northeastern Brazil where L. braziliensis is endemic. Since differences in TCR Vß repertoires based on DNA polymorphisms of the Vß region have been reported for African Americans and Caucasians (13), we compared TCR Vß usage in CL patients with that in healthy control individuals from the same area of endemicity, in order to minimize a possible bias in TCR Vß usage due to regional differences. We found that active CL did not lead to overexpression or clonal deletion of any Vß TCR. This finding rules out the possibility of superantigenic activity during cutaneous leishmaniasis, unlike what has been documented for mice infected with Plasmodium yoelii (39) and in humans infected with Brugia microfilariae (21). CL patients, however, did display a significant decrease in the expression of certain Vß families in both CD4+ and CD8+ T cells from peripheral blood.
We then observed whether this decrease in TCR Vß expression was confined to PBMCs or also extended to draining lymph node cells. Importantly, L. braziliensis infection is endemic in the area where patients were recruited, and as such, lymphadenopathy is commonly found as one of the first signs of infection (3). Surprisingly, when we compared cells from CL patients' peripheral blood with cells from draining lymph nodes, we found differences between these two compartments only in the CD8+ subset. Concerning CD8+ T cells, their role was first observed in mouse models of leishmaniasis (32), with which the ability of these cells to transfer DTH was demonstrated. Regarding human leishmaniasis, it was shown that higher proportions of Leishmania-reactive CD8+ T cells are present after therapy (11) and in individuals immunized against CL (30). An enrichment of Leishmania-reactive CD8+ T cells was observed in the inflammatory infiltrate of CL lesions, suggesting that the recruitment and/or proliferation of such cells could be favored by local immunoregulatory factors (10). CD8+ T cells also play an important role in the initial human immune response against Leishmania (41). These cells may inhibit the early dissemination of parasites (24) and participate in the immune effector mechanism of parasite elimination through the production of cytokines and through cytotoxic activation (20). In this sense, differences in the TCR Vß repertoires from CD8+ T cells of draining lymph nodes may indicate which T-cell clones are modulated in response to Leishmania: the decrease in Vß14 and Vß17 expression in CD8+ lymph node cells may reflect the sequestration of these T-cell clones in the lesion site, leading to their underrepresentation in draining lymph nodes, whereas the increase in Vß expression (Vß12 and Vß16) in CD8+ lymph node cells may reflect their role in the initial immune response to infection.
Since ex vivo staining of CD8+ T cells from draining lymph nodes showed a modulation in Vß expression, we investigated the effect of in vitro antigen stimulation on the expression of the TCR Vß repertoire. In these experiments, we chose to use SLA derived from L. amazonensis, since the immune responses to L. braziliensis and L. amazonensis antigens are similar and since L. amazonensis is easier to cultivate (45). We observed that most Vß TCRs were equally expressed in the presence or absence of antigen. The death of unstimulated clones was not pronounced; however, our analysis was based on the percentage of cells that expressed the different Vß families, precluding any speculation on this finding. The decrease in TCR Vß expression observed in this setting may be explained by an overt antigen stimulation leading to apoptosis; however, we also did not determine the number of apoptotic or viable cells after antigen stimulation. On the other hand, the increase in TCR Vß expression also observed in this study indicates that certain T-cell populations are able to selectively proliferate in vitro under specific antigen conditions (23). Oligoclonal expansion of T-cell clones has been documented in filariasis (17), Chagas'disease (31), and leishmaniasis (51). In the last study, it was shown that the Vß repertoire was skewed in lesions, with an overrepresentation of Vß3, Vß6.6/6.7, and Vß7. In our study, we did not find expansion of any of these particular TCRs after ex vivo analysis or in vitro antigen stimulation. In the work of Uyemura et al. (51), those T-cell clones for which a decrease in Vß frequency was observed may have resulted from apoptosis due to antigen overstimulation.
We then examined the TCR Vß repertoire after in vivo immunization with Leishmania antigen. The vaccine used in this study contained promastigotes of a reference L. amazonensis strain (41). In vivo immunization led to a consistent expansion of T-cell clones bearing different Vß families, in both CD4+ and CD8+ T cells. It seems likely that this is due to the antigen mixture that was used as a vaccine. It was surprising, however, that the TCR Vß repertoire was more diverse in CD4+ T cells, with a striking expansion in the TCRs Vß6.1, Vß11, and Vß20. In this vaccination experiment, ex vivo repertoire analysis was conducted 60 days after vaccination. It is possible that a similar expansion occurs during CL. However, since we cannot determine the exact time at which subjects from the area of endemicity are infected with the parasite, we also cannot analyze the TCR Vß repertoire exactly 60 days after infection.
Upon their first encounter with Leishmania, healthy volunteers displayed differences in the amounts of IFN- produced following vaccination (41). We then looked for an association between this amount of IFN- produced and TCR Vß expression in immunized volunteers. Interestingly, we found that high IFN- producers also showed an increased expression of Vß12, in both CD4+ and CD8+ T cells, and no such association was found for other Vß families. We next determined whether this association existed during Leishmania infection. To do so, we took advantage of the in vitro priming system (7, 48, 49). Priming of PBMCs from healthy volunteers (previously characterized as high IFN- producers) with live parasites led to a significant expansion of TCR Vß12 T cells which, in turn, also expressed IL-2R. Since we did not evaluate intracellular cytokine production, we can only speculate that Leishmania infection leads to TCR Vß12 T-cell activation and, possibly, IFN- production.
In the present study, out of all the Vß families examined, the frequency of TCR Vß12 cells was expanded in all situations tested, except in CL patients, in which it was decreased compared to the frequency in controls. Regarding Vß12 specifically, it has been shown that staphylococcal enterotoxin B preferentially induces the production of Th1 cytokines in TCR Vß12 T cells from healthy subjects and the production of Th2 cytokines in cells from atopic dermatitis patients (26). Also, an Actinobacillus actinomycetemcomitans extracellular preparation activated TCR Vß12 T cells (54). The identification of similar antigens in Leishmania is still deficient, probably due to the complexity of infection. Nonetheless, it has been shown that the early burst of IL-4 associated with susceptibility to leishmaniasis in mice is produced by a restricted population of Vß4 V8 CD4+ T cells after interaction with the LACK antigen (25). Similarly, the glycolipid -galactosylceramide is able to activate mouse NKT cells that express a TCR composed of an invariant V14-J18 chain paired, preferentially, with Vß8.2 or Vß7 chains (28). At this time we can only speculate that TCR Vß12 cells play an important role during CL. Nevertheless, it was surprising that this particular TCR was able to respond to in vitro antigen stimulation, vaccination, and in vitro priming. Studies are now in progress to elucidate the role played by TCR Vß12 cells in terms of the antigen they recognize during infection, whether these cells are present in lesions of CL patients, and, importantly, which cytokines they produce.
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ACKNOWLEDGMENTS |
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E.M.C., C.B., A.B. and M.B.-N. are senior investigators of the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). C.I.D.O. is the recipient of a FAPESB fellowship. This work was supported by CNPq and FIOCRUZ.
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FOOTNOTES |
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| J. Bacteriol. | J. Virol. | Eukaryot. Cell |
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| Microbiol. Mol. Biol. Rev. | Clin. Vaccine Immunol. | All ASM Journals |
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, P < 0.05.
