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. 2008 Jul;153(1):31–36. doi: 10.1111/j.1365-2249.2008.03666.x

CD26 expression on CD4+ T cells in patients with cutaneous leishmaniasis

R Jafari-Shakib *,1, S Ajdary †, Z Mohtasham Amiri ‡, A M Mohammadi §, K Nourijelyani , H Mortazavi **, M A Shokrgozar ††, B Nikbin *, A Khamesipour §
PMCID: PMC2432094  PMID: 18460019

Abstract

Surrogate marker(s) of protection in human leishmaniasis is not well defined. In this study, T helper 1 (Th1) and Th2 cytokine profiles and CD26 expression on CD4+ T cells in peripheral blood mononuclear cells of patients with healing or non-healing forms of cutaneous leishmaniasis (CL) stimulated with Leishmania antigens were assessed. The level of interferon (IFN)-γ production was significantly higher in patients with healing or non-healing forms of CL than in healthy controls, but it was not significantly different between the two patient groups. The level of interleukin-5 production was significantly higher in patients with the non-healing form of CL than in the two other groups. There was a significant increase in the level of CD26 expression on CD4+ T cells in patients with healing (P < 0·001) or non-healing (P = 0·025) forms of CL compared with the control group, but no significant difference was seen between the two patient groups. A weak positive correlation was seen between IFN-γ production and CD26 expression on CD4+ T cells of patients with the healing form of lesion (r = 0·54, P = 0·008), but this correlation was not observed in patients with the non-healing form of CL (r = 0·53, P = 0·078). Surface CD26 is not correlated with the clinical manifestation of CL or IFN-γ production. Therefore, CD26 is not a surrogate marker for IFN-γ production in CL.

Keywords: CD26, cutaneous leishmaniasis, IFN-γ, non-healing form

Introduction

Leishmaniasis represents a wide spectrum of clinical manifestations, depending upon the causative species of Leishmania and the host immune response, ranging from a self-healing cutaneous lesion to a lethal visceral form of disease [1]. Cutaneous leishmaniasis (CL) is caused by L. major or L. tropica or rarely by L. infantum in different parts of Iran [2]. CL is usually a self-healing skin lesion(s), but in rare cases the lesion may develop to a non-healing form which lasts for years and is refractory to available therapies [3]. In the murine model, generation of a T helper 1 (Th1)-type immune response accompanies a self-healing lesion and protection against further infection similar to human CL, whereas generation of a Th2-type immune response results in generalization of the disease and death [4,5]. Surrogate marker(s) of protection in human leishmaniasis is not well defined, but cure of CL usually accompanies protection against further infection and leishmanin skin test (LST) conversion [6–8]. The search for surrogate marker(s) of protection in leishmaniasis is highly desirable for the development of an effective vaccine [9]. Currently, LST and cytokine profile are used as indicators of the type and intensity of immune response generated in leishmaniasis [10].

CD26 is a proteolytic enzyme (dipeptidyl peptidase 4) expressed on a variety of cell types and its expression on T cells is enhanced by T cell activation [11,12]. Co-expression of CD26 and interferon (IFN)-γ is shown in skin biopsies of patients with the tuberculoid type of leprosy, but not in lepromatous leprosy [13]. A correlation was seen between a high level of CD26 cell surface expression and the production of Th1-like cytokines by T cell clones [14]. Interaction of adenosine deaminase on dendritic cells with CD26 on T lymphocytes leads to a marked increase in the production of Th1 and proinflammatory cytokines such as IFN-γ, tumour necrosis factor-α and interleukin (IL)-6 [15]. In multiple sclerosis patients, the CD4+ CD45RO+ CD26high subset was correlated with clinical severity and contained high levels of markers of Th1 effector functions, activation and central nervous system-transmigratory potential [16]. Strong up-regulation of CD26 expression on activated T cells by IL-12 but not by IL-4 suggests that CD26 may be used as a marker of Th1 subset [17]. Titration of sCD26/sCD30 in serum was also used to evaluate a Th1/Th2-type response in haemodialysis patients and during pregnancy [18,19]. The level of sCD26 and sCD30 in patients with visceral leishmaniasis (VL) or CL were studied and show that sCD30 is more relevant to clinical manifestation of leishmaniasis than sCD26 [20,21]. In the current study the possibility of CD26 expression as a marker of a Th1-type immune response on CD4+ T cells was studied in patients with healing or non-healing forms of CL. In this study, it was proposed to assess whether it is possible to use CD26 on CD4+ cells as a substitute for IFN-γ production.

Methods

Patients

Blood samples were collected from volunteers who were willing to donate blood samples and sign an informed consent. The following groups were included in the study: 23 parasitologically proven patients with the healing form of CL; 12 patients with the non-healing form of CL; and as control, 15 healthy volunteers from a non-endemic area with no history of leishmaniasis and no response to LST. The non-healing form is defined as CL with onset of more than 1 year if the causative agent is identified as L. major or onset of more than 2 years if the causative agent is L. tropica. Usually, the non-healing form of CL is refractory to several courses of antimonial therapy [3,7,22]. The proposal was approved by Ethical Committees of the CRTSDL and Tehran University of Medical Science, Tehran, Iran.

Isolation of mononuclear cells

Peripheral blood mononuclear cells (PBMCs) were separated from heparinized blood by histopaque 1077 (Sigma, St Louis, MO, USA) density centrifugation. The cells were frozen in aliquots of 90% fetal calf serum and 10% dimethylsulphoxide and stored in liquid nitrogen; plasma samples were collected and stored at −70°C for titration of sCD26 until use. Just prior to analysis, the cells were thawed in a 37°C water bath and washed twice with RPMI-1640. The cell viability was ascertained by trypan blue dye exclusion.

Lymphocyte proliferation

Peripheral blood mononuclear cells were cultured in RPMI-1640 (Sigma) medium supplemented with 100 U/ml penicillin, 100 μg/ml streptomycin, 2 mm l-glutamine, 10 mM HEPES (Gibco-BRL, Grand Island, NY, USA) and 15% heat-inactivated pooled human antibody serum. PBMCs were cultured in 96-well round-bottomed microculture plates (Greiner, Frickenhausen, Germany) at 106 cells/ml in 200 μl of complete medium stimulated with freeze–thawed L. major antigens (FTLM, 20 μg/ml protein content) or phytohaemagglutinin (PHA) 0·5% (Gibco-BRL) and incubated at 37°C, 5% CO2 in a humidified atmosphere. FTLM was prepared by harvesting L. major (MRHO/IR/75/ER) at the stationary phase, harvested promastigotes were washed three times and then freeze–thawed five times, and the protein concentration was measured using Lowry's method. Optimal concentrations of antigen and mitogen needed for proliferation assay were determined prior to the experiment. The antigen-stimulated culture plates were incubated for 7 days and pulsed with 0·5 μc/well of [3H]-thymidine (Amersham, Little Chalfont, UK) for the last 18 h of incubation. Cells were then harvested on fibreglass filters using a multi-channel cell harvester and the incorporation of [3H]-thymidine into DNA was measured by scintillation counting. All tests were performed in triplicate and for each set of samples the mean value was used. The stimulation index (SI) was calculated by dividing the mean counts per minute (cpm) of stimulated wells by the mean cpm of unstimulated wells.

Cytokine measurement and flow cytometry

Peripheral blood mononuclear cells were cultured in complete RPMI-1640 medium at 106 cells/ml in 24-well flat-bottomed microculture plates (Greiner) in 1 ml volume stimulated with FTLM and incubated for 7 days. The culture supernatants were recovered and stored at −70°C for cytokine assay and the cells were examined for the expression of CD26 using flow cytometry with conjugated antibodies directed against the cell surface markers fluorescein isothiocyanate-conjugated anti-CD3, R-phycoerythrin and cyanine Cy5-conjugated anti-CD4 and phycoerythrin-conjugated anti-CD26 (Dako, Glostrup, Denmark). After adequate washing and fixing with 2% formaldehyde, the cells were analysed on fluorescence activated cell sorter (FACScan) flow cytometer (Becton Dickinson, Mountain View, CA, USA) using Lysis 2 software. Isotype-matched control antibodies were used to detect non-specific binding to cells.

Interferon-γ and sCD26 (Bender MedSystems, Vienna, Austria), IL-5 and IL-10 (Pharmingen, San Diego, CA, USA) were measured by the sandwich enzyme-linked immunosorbent assay method according to the manufacturer's instructions. The thresholds of IFN-γ, IL-5 and IL-10 detection were 7·5, 15 and 15 pg/ml, respectively, and for sCD26 was 78 ng/ml. sCD26 was analysed in only a percentage of volunteers (aaa18 healing lesions, seven non-healing lesions and 12 healthy controls).

Statistical analysis

Data were analysed using spss statistical software (version 11·0, 2003; SPSS, Inc., Chicago, IL, USA). The differences of sample medians were tested by Kruskal–Wallis and Mann–Whitney U-tests and P < 0·05 was considered significant.

Results

Age, sex distribution, duration of lesion and LST response of different groups of volunteers are summarized in Table 1. There was no significant difference between the groups in baseline data.

Table 1.

Age, gender, duration of lesion and leishmanin skin test (LST) response of the volunteers.

Groups
Control Healing Non-healing
Age (years, mean) 33·0 ± 5·8 32·4 ± 14·1 27·5 ± 19·6
Male/female ratio 13/2 16/7 10/2
Duration (month, mean) 0 5·5 ± 5·4 86·8 ± 44·5
LST > 5 mm 0 61·1% 83·3%
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Lymphoproliferative response

The results of proliferative responses of different groups are shown in Fig. 1. There was a significant (P < 0·001) difference between SI of patients with the healing form of lesion and SI of patients with the non-healing form of lesion in comparison with the control group. No significant difference was seen between the SI of patients with the non-healing form of lesion and SI of patients with the healing form of lesion. A high response to PHA was seen in all three groups, with no significant difference between the groups (data are not shown).

Fig. 1.

Fig. 1

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Lymphoproliferative responses of peripheral blood mononuclear cells to freeze–thawed L. major antigen in different groups.

Cytokine production

Production of IFN-γ, IL-5 and IL-10 was titrated in the supernatants of PBMCs stimulated with FTLM. The IFN-γ production in different groups is shown in Fig. 2. Patients with healing and non-healing forms of lesion produced a significantly (P < 0·001) higher amount of IFN-γ than the control group. The level of IFN-γ was not significantly different between the group of patients with the healing form and the group of patients with the non-healing form of lesion.

Fig. 2.

Fig. 2

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Interferon (IFN)-γ level in supernatants of peripheral blood mononuclear cells stimulated with freeze–thawed L. major antigen in different groups.

Interleukin-5 was titrated as a Th2-type cytokine, and the level of IL-5 in culture supernatants of PBMCs stimulated with FTLM is shown in Fig. 3. The level of IL-5 production was significantly higher only in the group of patients with the non-healing form of lesion compared with that of patients with the healing form of lesion (P = 0·02) and the control group (P = 0·002). No considerable levels of IL-10 were produced by PBMCs of any group in response to FTLM (data not shown).

Fig. 3.

Fig. 3

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Interleukin (IL)-5 level in supernatants of peripheral blood mononuclear cells stimulated with freeze–thawed L. major antigen in different groups.

Flow cytometry results

The percentage of CD26+ cells in the CD4+ T cell population on day 7 of PBMC culture with or without stimulation with FTLM is shown in Fig. 4. There was no significant difference in the percentage of CD26+ cells in the population of CD4+ T cells of PBMCs of the three groups, either stimulated or unstimulated with FTLM.

Fig. 4.

Fig. 4

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Comparison of the percentage of CD26+ cells in the CD4+ T cell population in three groups before and after freeze–thawed L. major antigen stimulation.

The level of CD26 expression on CD4+ T cells was not significantly different in the groups when the PBMCs were not stimulated (aaa117·6, 103·6, 92·9 as median for the healing and non-healing forms of lesion and controlgroups respectively), but there was a significant difference (P < 0·001) between the three groups after stimulation with FTLM (aaa204·7, 142·0, 102·1 as median for the healingand non-healing forms of lesion and control groups respectively). PBMCs stimulated with FTLM in both patients with the healing and non-healing forms of lesion showed a significantly higher level of CD26 expression on CD4+ T cells in comparison with the control group (P < 0·001 and P = 0·025 respectively), but there was no significant difference between the two patient populations (P = 0.053) (Fig. 5).

Fig. 5.

Fig. 5

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Comparison of the level of CD26 expression on CD4+ T cells of peripheral blood mononuclear cells in three groups before and after freeze–thawed L. major antigen stimulation.

Correlation between the level of CD26 expression on CD4+ T cells and IFN-γ production

A weak correlation (r = 0·54, P = 0·008) was seen between the level of CD26 expression on CD4+ T cells and IFN-γ production after PBMC stimulation in patients with the healing form of lesion, but no correlation was seen between the level of CD26 expression on CD4+ T cells and IFN-γ production in patients with the non-healing form (r = 0·53, P = 0·078).

sCD26 level and correlation between CD26 expression

sCD26 in serum was measured in three groups; the level of sCD26 was 628·2 ± 114·5 in patients with the healing form of lesion, 709·4 ± 84 in patients with the non-healing form of lesion and 603·6 ± 106·2 in the healthy control group. No linear correlation was seen between the level of CD26 expression on CD4+ T cells after antigen stimulation and the level of sCD26 in plasma was r = −0·27 in the groups of healing (n = 18) and r = 0·39 non-healing lesions (n = 7).

Correlation of sCD26 with IFN-γ and IL-5 production

As shown in Table 2, no linear correlation was seen between the levels of IFN-γ or IL-5 production in FTLM-stimulated PBMCs and plasma level of sCD26 in the healing (n = 18) or non-healing forms (n = 7) of lesion.

Table 2.

Correlation of sCD26 in serum with interferon (IFN)-γ and interleukin (IL)-5 production of peripheral blood mononuclear cells in patients group after freeze–thawed L. major antigen stimulation.

sCD26 (ng/ml)
Healing (n = 18) Non-healing (n = 7)
IFN-γ (pg/ml)
 r −0·219 0·108
 P-value 0·38 0·82
IL-5 (pg/ml)
 r 0·08 −0·073
 P-value 0·75 0·87
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Discussion

Surrogate markers of cure and protection in human leishmaniasis are not yet defined. Usually in vivo LST and in vitro Th1/Th2 cytokine profiles are used to assess the immune status in leishmaniasis, which is not always precise. A simple quantitative test for surrogate markers of protection would highly facilitate vaccine development against leishmaniasis [9].

In the present study, the lymphoproliferative responses were significantly higher in the two groups of patients compared with controls (Fig. 1); the data on the lymphoproliferative responses of patients with the healing form of lesion is similar to those reported earlier. However, in contrast, no significant difference was seen in the responses of the healing form of lesion patients compared with those of the non-healing form of lesion [6,23].

A significantly higher amount of IFN-γ was produced by PBMCs of the two patient groups compared with the control group (Fig. 2); a significantly higher level of IL-5 was seen in patients with the non-healing form of lesion (Fig. 3). These data indicate a possible Th1/Th2 mixed response in the non-healing form and Th1 response in the healing form of lesion. The Th1 response in the healing form of lesion is consistent with other studies, which showed a Th1 cytokine profile in patients with the healing form [6,7,22,24]. Trujillo et al. [24], in a study conducted in Colombia, showed a high level of IFN-γ in patients with localized CL caused by L. viannia panamenesis. Studies performed in Iran showed high levels of IFN-γ and IFN-γ mRNA in Iranian CL patients [6,7,22]. In the current study, contrary to previous studies conducted in Iran [6,7,22], the level of IFN-γ in patients with the non-healing form of lesion was not significantly lower than the patients with the healing form of lesion. Ajdary et al. [6] and Mahmoodi et al. [22] showed no or a low level of IFN-γ in patients with the non-healing form of lesion when the PBMCs were stimulated with soluble Leishmania antigens (SLA). Habibi et al. [7] showed a low level of IFN-γ and IL-12 mRNA expression in PBMCs of patients with the non-healing form of lesion stimulated with either SLA or gp63. Results from the current study are very similar to the results of the study conducted by Da-Cruz et al. [23] in Brazilian patients with mucocutaneous lesion caused by L. brasiliensis, in which both IFN-γ and IL-5 production were seen in response to disrupted promastigotes. The controversy seen in the human immune response against leishmaniasis is due to the fact that a small sample size with various clinical pictures was used in each study. With the diversity of clinical manifestations of leishmaniasis to obtain a clear picture of the nature of immune response generated in leishmaniasis, investigators need to include a large enough sample size, which is not affordable in most endemic areas; also, different antigens are used to stimulate PBMCs in different studies. A report has shown that, in an animal model, treatment of leishmaniasis influences the intensity of the Th1/Th2 immune response [25]; patients recruited in the studies were not receiving uniform standard therapy, which might explain these differences between studies.

No IL-10 was shown in the culture of PBMCs of the patients or control volunteers in this study, corresponding with the results of other studies [6,7,26].

It was shown that expression of CD26 is associated preferentially with a Th1 response in patients with tuberculoid but not lepromatous leprosy [13] and patients with allergy [14]. In this study, there was no difference between the percentage of CD26+ cells in the CD4+ T cell population (Fig. 4) in either stimulated or unstimulated PBMCs. When CD26 expression was analysed with mean channel flow cytometry, no significant difference in CD26 expression on CD4+ T cells was seen between different groups of unstimulated PBMCs. However, after stimulation, the CD26 expression was increased significantly in both patients with healing as well as non-healing forms of lesion. A slight but not significant increase of CD26 expression was seen in the control group after stimulation, which is in agreement with the low level of IFN-γ production and low SI.

There was no correlation between CD26 expression on CD4+ T cells and sCD26 in either of the two patient groups, which might be due to the fact that high levels of CD26 expression are reported on other cells, such as keratinocytes, which are affected in CL [27]. The higher level of sCD26 in serum might be due to release of CD26 from the surface of different cell types. Keane et al. [28] showed no correlation between enzymatic activity of serum CD26 and IFN-γ production by PBMCs culture in aquired immune deficiency syndrome (AIDS) patients and concluded that the study could not support CD26 enzyme activity as a marker of Th1 response. Rogala et al. [29] showed that CD26 is not a suitable marker to discriminate the Th1/Th2 response in episodic atopic bronchial asthma and diabetes mellitus type 1 patients. Ajdary et al. [20] showed no significant difference in sCD26 levels in asymptomatic VL and active VL caused by L. infantum, although L. infantum-infected asymptomatic individuals showed evidence of a Th1-type response, and a Th2 response in active disease. In a previous study [21], the level of sCD26 was not different between active lesions of anthroponotic CL and healthy controls, but the level of sCD26 was significantly higher in the non-healing form of lesion. In the present study, a correlation was seen between IFN-γ production and CD26 expression on CD4+ T cells after PBMC stimulation only in patients with the healing form, but not in patients with the non-healing form, of lesion in spite of a high level of IFN-γ production. It appears that CD26 expression on CD4+ T cells or sCD26 should not be used as a marker to evaluate the Th1 response in CL patients.

Acknowledgments

We thank Haideh Darabi, Maliheh Vaziri, Amina Kariminia and Farhad Riazi-Rad from the Department of Immunology, Pasteur Institute and also Ebrahim Eskandari from the Center for Research and Training in Skin Disease and Leprosy (CRTSDL) for technical assistance, and Dr Farrokh Modabber for reviewing the manuscript. This work was conducted at the Department of Immunology, Pasteur Institute, and was supported by Department of Immunology, TUMs and CRTSDL and the Deputy of Research and Technology, Ministry of Health and Medical Education.

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