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Selective Decrease in Circulating V24⁺V11⁺ NKT Cells During HIV Type 1 Infection¹

Hans J. J. van der Vliet^*, B. Mary E. von Blomberg, Mette D. Hazenberg, Nobusuke Nishi^*, Sigrid A. Otto, Birgit H. van Benthem^¶, Maria Prins^¶, Frans A. Claessen, Alfons J. M. van den Eertwegh^*, Giuseppe Giaccone^*, Frank Miedema, Rik J. Scheper^2,*, and Herbert M. Pinedo^*

Departments of ^* Medical Oncology, Pathology, and Internal Medicine, Free University Medical Center, Amsterdam, The Netherlands; Department of Clinical Viro-Immunology, CLB, and the Laboratory for Experimental and Clinical Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and ^¶ Cluster of Infectious Diseases, Municipal Health Service, Amsterdam, The Netherlands

	Abstract

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CD1d-restricted NKT cells express an invariant TCR and have been demonstrated to play an important regulatory role in a variety of immune responses. Invariant NKT cells down-regulate autoimmune responses by production of type 2 cytokines and can initiate antitumor and antimicrobial immune responses by production of type 1 cytokines. Although defects in the (invariant) V24⁺V11⁺ NKT cell population have been observed in patients with cancer and autoimmune diseases, little is known regarding the protective role of V24⁺V11⁺ NKT cells in human infectious disease. In a cross-sectional study in HIV-1-infected individuals, we found circulating numbers of V24⁺V11⁺ NKT cells to be reduced, independent of CD4⁺ T cell counts, CD4:CD8 ratios, and viral load. Because a small minority of V24⁺V11⁺ NKT cells of healthy donors expressed HIV-1 (co)receptors and the vast majority of V24⁺V11⁺ NKT cells in HIV-1-infected individuals expressed the Fas receptor, the depletion was more likely due to Fas-mediated apoptosis than to preferential infection of V24⁺V11⁺ NKT cells by HIV-1. A longitudinal cohort study, in which patients were analyzed before seroconversion and 1 and 5 years after seroconversion, demonstrated that a large proportion of the depletion occurred within the first year postseroconversion. In this longitudinal study no evidence was found to support an important role of V24⁺V11⁺ NKT cells in determining the rate of progression during HIV-1 infection.

	Introduction

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Natural killer T cells constitute a lymphocyte lineage sharing characteristics of both T cells and NK cells. NKT cells display an extremely restricted TCR repertoire, in humans consisting of a V24 chain preferentially paired with a V11 chain, and recognize Ag in the context of the monomorphic CD1d Ag-presenting molecule (1, 2, 3). Although natural ligands are not known, NKT cells have been shown to recognize the -anomeric glycolipid -galactosylceramide (-GalCer)³ when presented by CD1d (4, 5, 6). A potential role of NKT cells in the regulation of immune responses has been hypothesized because of their capacity to rapidly release large amounts of IL-4 and IFN- upon activation (3, 7). Indeed, NKT cells have now been shown to play crucial roles in various immune responses, including antitumor, autoimmune, and antimicrobial immune responses (summarized in Ref. 8). Their regulatory role in immune responses that require opposite regulatory pathways has been attributed to an apparent flexibility of NKT cells with regard to their predominant cytokine profile. NKT cell-derived Th1 cytokines (e.g., IFN-) are important in the initiation of antitumor immune responses while NKT cell-derived Th2 cytokines (e.g., IL-4 and IL-10) are involved in down-regulation of autoimmune responses (9, 10).

Murine NKT cells participate in immune responses to a range of different infectious agents, including Listeria, Toxoplasma, Mycobacteria, Salmonella, Plasmodium, and hepatitis (8, 11). The granulomatous reaction to Mycobacterium tuberculosis is dependent on NKT cells, and mycobacterial infection stimulates IFN- production by NKT cells (12, 13). In MHC class II-deficient mice, NKT cells mediate the development of cell-mediated immunity to Toxoplasma gondii infection (14), and during infection with Plasmodium yoelii there was an increase in liver NKT cells, which directly inhibited growth of pathogen in hepatocytes in vitro via an IFN--dependent mechanism (15). Interestingly, -GalCer-mediated activation of NKT cells was recently shown to mediate protection against both murine malaria and hepatitis B. IFN- was essential for the anti-malaria effect of -GalCer, while its antiviral effects were mediated by both IFN- and IFN- (11, 16).

At present, little is known about the potential role of NKT cells in human infectious diseases. Although NKT cells bridge innate and adaptive immune responses, both of which are important in controlling HIV infection (17, 18), and have been reported to exert antiviral effects via IFNs that are also capable of inhibiting HIV replication (19), no data are available on the role of NKT cells in HIV infection. In this work, we studied the size of the circulating V24⁺V11⁺ NKT cell population during HIV-1 infection and evaluated whether differences in the size of the V24⁺V11⁺ NKT cell population would affect HIV-1 disease progression.

	Materials and Methods

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Study population

Cross-sectional analyses were performed on a group of 46 healthy adult volunteers (mean age, 42 years; range, 21–83 years; 19 males and 27 females) and a group of 50 patients (mean age, 41 years; range, 19–59 years; 42 males and 8 females) with known HIV-1-positive status attending the outpatient clinic of the Department of Internal Medicine of the Free University Medical Center (Amsterdam, The Netherlands). Of the 50 HIV-1-infected patients, 37 received highly active antiretroviral therapy (HAART). Mean CD4⁺ T cell count was 362 cells/µl (range, 10–1180); mean CD4:CD8 ratio was 0.2 (range, <0.1–1); and mean viral load was 53194 copies/ml, viral load being undetectable in 30 patients. The longitudinal cohort study was performed using cryopreserved PBMC of 87 participants of the Amsterdam cohort studies on AIDS and HIV-1 infection in homosexual men (this study, which is ongoing, was initiated in 1984 in a collaboration between the Amsterdam Municipal Health Service, the Academic Medical Center at the University of Amsterdam, and the Central Laboratory of The Netherlands Red Cross Blood Transfusion Service). For cryopreservation, a computerized freezing device was used that resulted in optimal quality of viably frozen cells for functional studies (20), and frozen blood samples were stored in liquid nitrogen.

Flow cytometric analysis

In the cross-sectional study, leukocytes were prepared from heparinized peripheral blood using the ImmunoPrep Reagent System (Coulter, Miami, FL) and lymphocyte numbers were calculated using Simultest LeucoGATE reagent in combination with SimulSET software (BD Biosciences, San Jose, CA). Analysis of V24⁺V11⁺ NKT cells in patients from the cohort study was performed on cryopreserved peripheral blood samples. Typically, 1–5 x 10⁵ viable lymphocytes were evaluated for calculation of the frequency of V24⁺V11⁺ NKT cells. The following Abs were used: FITC-labeled anti-human V24 mAb, PE- and biotin-labeled anti-human V11 mAb (Immunotech, Marseille, France), R-PE-Cy5-labeled CD3 and CD4 mAb, R-PE-Cy5-labeled streptavidin (DAKO, Glostrup, Denmark), PE-labeled CD95 mAb (BD Biosciences), and PE-labeled CCR5 mAb (BD PharMingen, San Diego, CA). CD4/CD8 SimulSET was purchased from BD Biosciences. Flow cytometric analysis was performed on a FACStar^Plus equipped with an argon ion laser (BD Biosciences).

Plasma HIV-1 RNA detection

Plasma HIV-1 RNA load was assessed using the ultrasensitive AMPLICOR HIV-1 MONITOR test version 1.5 (Roche Diagnostics, Indianapolis, IN).

Cell cultures

PBMC from healthy volunteers were allowed to adhere to culture flasks for 2 h at 37°C. Immature monocyte-derived dendritic cells (moDC) were then prepared from the adherent cells during a 7-day culture in the presence of recombinant human (rh)IL-4 (1000 U/ml; Central Laboratory of The Netherlands Red Cross Blood Transfusion Service Sanquin Blood Supply Foundation, Amsterdam, The Netherlands) and rhGM-CSF (100 ng/ml; Kirin Brewery, Gunma, Japan) in IMDM (BioWhittaker, Verviers, Belgium) supplemented with 10% FCS, 0.01 mM 2-ME, and 50 U/ml penicillin-streptomycin. Immature moDC were then matured for 3 days with rhTNF- (50 ng/ml; Cetus, Amsterdam, The Netherlands) in the presence of 100 ng/ml -GalCer (KRN7000). Mature -GalCer-loaded moDC were washed and cocultured for 7 days with autologous nonadherent PBMC.

-GalCer

-GalCer ((2S,3S,4R)-1-O-(-D-galactopyranosyl)-2-(N-hexacosanoylamino)- 1,3,4-octadecanetriol) was synthesized by the Pharmaceutical Research Laboratory of the Kirin Brewery and dissolved in 100% DMSO. Final concentration of DMSO in cultures was 0.1%.

Statistical analysis

Statistical analyses were performed using the Mann-Whitney U test, Wilcoxon matched pairs test, Student t test, and rank correlation test. Cox proportional hazards analysis was used to evaluate the prognostic value of V24⁺V11⁺ NKT cells for HIV-1 disease progression. A value of p < 0.05 was considered significant.

	Results

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Circulating V24⁺V11⁺ NKT cell numbers are decreased during HIV-1 infection

Cross-sectional analysis of a group of 50 HIV-1-infected and 46 healthy individuals revealed that circulating numbers of V24⁺V11⁺ NKT cells (i.e., T cells expressing both the TCR V24 and V11 chains) were significantly lower in HIV-1-infected individuals (HIV-1 group: median, 71.5; interquartile range (IQR), 25–257; and control group: median, 586.5; IQR, 308-1249; p < 0.0001; Mann-Whitney U test, Fig. 1, left panel). Cell numbers were calculated per 1 x 10⁶ lymphocytes to correct for lymphopenia and lymphocytosis. Although the V24 and V11 mAb used in our analyses do not molecularly identify the invariant TCR rearrangement of NKT cells, their combined use was shown to be highly specific for invariant NKT cells and allows calculation of circulating cell numbers (8, 21). Circulating numbers of V24⁺V11^- T cells were also reduced (HIV-1 group: median, 1336; IQR, 817-2136; and control group: median, 1512; IQR, 1194–2682; p = 0.03, Fig. 1, middle panel), but circulating numbers of T cells expressing only the V11 chain were comparable in HIV-1-infected individuals and in controls (HIV-1 group: median, 3750; IQR, 2886–5092; and control group: median, 4534; IQR, 3741–5163; p = 0.11, Fig. 1, right panel). Patients receiving and not receiving HAART had comparable circulating V24⁺V11⁺ NKT cell numbers (Fig. 1, left panel; p = 0.31). Further evaluation revealed that there was no significant correlation between circulating V24⁺V11⁺ NKT cell numbers and CD4:CD8 ratio (Fig. 2; correlation coefficient (r) = 0.12, p = 0.42, Spearman rank correlation test), CD4⁺ T cell counts (Fig. 2; r = -0.06, p = 0.67), or HIV-1 RNA viral load (Fig. 2; r = 0.18, p = 0.21). Similarly, there was no significant correlation between circulating V24⁺V11⁺ NKT cell numbers and HIV-1 RNA viral load (r = 0.15, p = 0.66) or CD4⁺ T cell counts (r = 0.14, p = 0.69) when analysis was performed on patients not receiving HAART.

View larger version (12K): [in this window] [in a new window]   FIGURE 1. Decrease in circulating V24+V11+ NKT cells during HIV-1 infection. Shown is a significant decrease in V24+V11+ NKT cells (p < 0.0001, Mann-Whitney U test) and in V24+V11- T cells (p = 0.03), but not in V24-V11+ T cells (p = 0.11). Horizontal lines indicate the median. , Patients receiving HAART; , patients not receiving HAART. Data represent a cross-sectional analysis of 50 HIV-1-positive patients and 46 healthy adult volunteers.

View larger version (12K): [in this window] [in a new window]   FIGURE 2. Correlation among circulating V24+V11+ NKT cell numbers, CD4:CD8 ratio, CD4+ T cell counts, and viral load. No significant correlation was found between circulating V24+V11+ NKT cells and CD4:CD8 ratio (r = 0.12, p = 0.42, Spearman rank correlation test), CD4+ T cell counts (r = -0.06, p = 0.67), or HIV-1 RNA viral load (r = 0.18, p = 0.21). Data represent cross-sectional analyses of 50 HIV-1-positive patients.

Kinetics of V24⁺V11⁺ NKT cell depletion during HIV-1 infection

Because the exact duration of HIV-1 infection had not been recorded in the cross-sectional analysis, we set out to confirm and extend our findings by analyzing the frequency of V24⁺V11⁺ NKT cells in cryopreserved PBMC of the Amsterdam cohort on HIV-1 infection in homosexual men. V24⁺V11⁺ NKT cell frequencies were determined at three time points: before seroconversion, 1 year postseroconversion, and 5 years postseroconversion. Fig. 3A shows that the frequency of V24⁺V11⁺ NKT cells (expressed as a percentage of T cells) significantly decreased during HIV-1 infection. The preseroconversion V24⁺V11⁺ NKT cell frequency (median, 0.03; IQR, 0.01–0.08; n = 48) was significantly lower than in our control group (median, 0.08; IQR, 0.04–0.17; p = 0.02, Mann-Whitney U test). This frequency decreased to 0.02 (IQR, 0.01–0.04; n = 82) and 0.01 (IQR, 0–0.02; n = 50) at 1 and 5 years postseroconversion, respectively (preseroconversion vs 1 year postseroconversion, p < 0.0001 (Wilcoxon matched pairs test); preseroconversion vs 5 years postseroconversion, p < 0.0001; 1 vs 5 years postseroconversion, p = 0.0002). In contrast, the frequency of single V11⁺ T cells (expressed as a percentage of T cells) did not significantly change in the course of HIV-1 infection (preseroconversion vs 5 years postseroconversion, p = 0.054). Data are expressed as a percentage of T cells to correct for differences in total T cell numbers over time. Fig. 3B shows representative flow cytometric dot plots from one individual.

View larger version (25K): [in this window] [in a new window]   FIGURE 3. Selective depletion of V24+V11+ NKT cells during HIV-1 infection. Cryopreserved PBMC samples of participants from the Amsterdam cohort studies on AIDS and HIV-1 infection in homosexual men were analyzed preseroconversion and at 1 and 5 years postseroconversion. A, A decrease in V24+V11+ NKT cells (preseroconversion vs 5 years postseroconversion, p < 0.0001; Wilcoxon matched pairs test) but not in V24-V11+ T cells (preseroconversion vs 5 years postseroconversion, p = 0.054). Data are expressed as a percentage of T cells; median, IQR, minimum, and maximum are shown. B, Sequential dot plots of CD3+ cells from one individual.

Expression of CD4, CCR5, and CD95 on V24⁺V11⁺ NKT cells

One of the potential causes of the selective decrease in the size of the circulating V24⁺V11⁺ NKT cell population could be their preferential infection by HIV-1. The HIV-1 virion enters its target cell through a sequence of conformational shifts initiated by binding to CD4. Primary HIV-1 infection is established with non-syncytium-inducing CCR5 coreceptor using HIV-1 variants (22, 23, 24, 25). First, we studied CD4 expression on V24⁺V11⁺ NKT cells of healthy volunteers both before and after activation. CD4 expression was observed on 25 ± 8% (n = 5; data not shown) of circulating V24⁺V11⁺ NKT cells. Although ligand-specific activation of V24⁺V11⁺ NKT cells using -GalCer-loaded moDC uniformly resulted in the expression of high levels of the activation marker CD25 (data not shown), it did not result in a significant up-regulation of CD4 expression on V24⁺V11⁺ NKT cells (40 ± 21%, n = 5, p = 0.21, paired Student’s t test). Furthermore, because only 1.6 ± 1.9% (n = 4) of V24⁺V11⁺ NKT cells was found to express both CD4 and CCR5, we think that it is unlikely that direct infection accounts for the depletion of the V24⁺V11⁺ NKT cell population (Fig. 4A).

View larger version (19K): [in this window] [in a new window]   FIGURE 4. Expression of CD4, CCR5, and Fas on V24+V11+ NKT cells. Shown are representative flow cytometric dot plots of expression of CD4 and CCR5 on V24+V11+ NKT cells of a healthy donor (A) and of Fas expression on V11+ T cells of an HIV-1-infected patient (B).

Prognostic relevance of the size of the V24⁺V11⁺ NKT cell pool on HIV-1 progression

Because the circulating V24⁺V11⁺ NKT cell frequency showed strong interindividual variability, we evaluated whether the size of the circulating V24⁺V11⁺ NKT cell pool could predict disease progression during HIV-1 infection. Participants of the Amsterdam cohort on HIV-1 infection in homosexual men were split into two groups based on whether they had a circulating V24⁺V11⁺ NKT cell frequency above or below the group median. The relative hazard (RH) of the group of participants with above-median circulating V24⁺V11⁺ NKT cell frequencies was then compared with the group of participants with below-median circulating V24⁺V11⁺ NKT cell frequencies with respect to the following AIDS-related endpoints: progression to AIDS (27), death from an AIDS-related cause, CD4⁺ T cell counts < 200/ml, and conversion to a syncytium-inducing viral variant (SI conversion). Analyses performed preseroconversion, 1 year postseroconversion, and 5 years postseroconversion clearly showed that relatively higher V24⁺V11⁺ NKT cell frequencies were not predictive of a better outcome in HIV-1-infected patients (Table I). Similar results were obtained in multivariate analyses where results were corrected for viral HIV-1 RNA load and CD4⁺ T cell counts (data not shown).

View this table: [in this window] [in a new window]   Table I. Effect of the size of the V24+V11+ NKT cell pool on HIV-1 progressiona

	Discussion

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The disappearance of V24⁺V11⁺ NKT cells during HIV-1 infection is not likely to be the result of viral infection per se, because circulating V24⁺V11⁺ NKT cell frequencies were recently reported to be normal during hepatitis C viral infection (21). Several factors could contribute to the depletion of the circulating V24⁺V11⁺ NKT cell population, including sequestration, preferential infection, and activation-induced cell death. First, the rise in CD4⁺ and CD8⁺ T cell numbers during the first 4 wk of HAART is generally believed to be due to redistribution of previously sequestered memory lymphocytes from lymphoid tissues to the circulation (28). No relation between viral load and circulating V24⁺V11⁺ NKT cell numbers could be found, and in several patients who showed CD4⁺ T cell responses upon institution of HAART circulating V24⁺V11⁺ NKT cell numbers remained low (data not shown). However, to formally exclude the possibility that the depletion of the V24⁺V11⁺ NKT cell population is the result of sequestration in the periphery, we are now systematically evaluating the effects of HAART on circulating V24⁺V11⁺ NKT cell numbers. Second, it has been reported that the HIV-1 virion enters a target cell through a sequence of conformational shifts initiated by the binding of CD4 (25). Previously, we and others have reported that CD4 expression could be observed on a minority of circulating V24⁺V11⁺ NKT cells (29, 30). Although CD8⁺ T cells can express CD4 upon activation, allowing HIV entry (31, 32), we found no evidence for a similar activation-induced up-regulation of CD4 expression on V24⁺V11⁺ NKT cells. Because only 1.6 ± 1.9% of V24⁺V11⁺ NKT cells expressed both CD4 and the coreceptor CCR5, we believe that it is unlikely that physical infection of V24⁺V11⁺ NKT cells is responsible for the population depletion. Third, several reports indicate that ligation of the Fas receptor by FasL is an important factor involved in HIV-associated lymphocyte depletion. T cells from HIV-infected patients have been reported to exhibit both increased Fas receptor expression and enhanced susceptibility to Fas-mediated death (33, 34). Of note, both FasL expression on PBMC and plasma levels of soluble FasL are increased in HIV-positive patients (35, 36, 37). We found the Fas receptor to be expressed by the vast majority of residual circulating V24⁺V11⁺ NKT cells. Because the proportion of V24⁺V11⁺ NKT cells expressing the Fas receptor was significantly higher than that of single V11⁺ T cells, Fas-induced apoptosis might contribute to the observed selective depletion of the V24⁺V11⁺ NKT cell population. HIV-1 infection has been demonstrated to increase cell division and death rates mainly by causing persistent immune activation (38). Therefore, one could hypothesize that the observed depletion of the V24⁺V11⁺ NKT cell population is the result of a continuous process of activation-induced cell death. Because renewal of invariant NKT cells was demonstrated to be slow in both mouse and human (39).⁴ this could further contribute to the decrease in the size of the V24⁺V11⁺ NKT cell population.

Infection with HIV-1 has been associated with various autoimmune syndromes and malignancies (40, 41, 42). Because defects in the invariant NKT cell population were reported in both animals and patients suffering from autoimmune disease or malignancy (8, 43, 44, 45, 46), it is tempting to speculate that the increased frequency of autoimmune phenomena and malignancies during HIV-1 infection is related to a decrease in the size of the V24⁺V11⁺ NKT cell population. Because activated NKT cells could down-regulate hepatitis B viral replication in mice through production of IFN- and IFN- (11), cytokines previously reported to inhibit HIV replication (19), we hypothesized that V24⁺V11⁺ NKT cells could slow down progression during HIV-1 infection. However, our data could not demonstrate a statistically significant relation between the circulating V24⁺V11⁺ NKT cell frequency and several AIDS-related disease endpoints. In contrast to what we expected, individuals with higher preseroconversion or 1 year postseroconversion V24⁺V11⁺ NKT cell frequencies tended to have even higher RHs, suggesting a potential immunosuppressive effect of V24⁺V11⁺ NKT cells. Recent evidence indeed suggests that the natural role of NKT cells could be immunosuppressive in nature by predominant production of Th2 cytokines (47). Of interest, synthetic glycolipid analogs of -GalCer were shown to differentially affect the cytokine profile of NKT cells (48). Therefore, because high-affinity TCR ligands preferentially induce Th1-type responses in T cells (49), stimulation of NKT cells by ligands that result in high-affinity interactions could shift NKT cell cytokine production toward a Th1 profile, thereby enhancing the establishment of a proinflammatory immune response (50). This would favor both antivirus and antitumor immune reactivity but could also increase the frequency of autoimmune phenomena during HIV infection. Therefore, although we report in this work that the size of the circulating V24⁺V11⁺ NKT cell population does not affect the progression rate to several clinical and immunological endpoints, further studies are needed to examine the relationship between the cytokine profile of V24⁺V11⁺ NKT cells and HIV-1 disease progression.

In conclusion, in this study we demonstrate for the first time the preferential depletion of the immunoregulatory V24⁺V11⁺ NKT cell population during HIV-1 infection. Although this depletion is likely to contribute to the development of immunodeficiency, our data do not provide evidence to support an important role of V24⁺V11⁺ NKT cells in determining the rate of progression during HIV-1 infection.

	Footnotes

 
¹ This work was supported by a Spinoza grant and Grant NR 920-03-142 from The Netherlands Organization for Scientific Research.

² Address correspondence and reprint requests to Dr. Rik J. Scheper, Department of Pathology, Free University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. E-mail address: rj.scheper{at}vumc.nl

³ Abbreviations used in this paper: -GalCer, -galactosylceramide; HAART, highly active antiretroviral therapy; rh, recombinant human; RH, relative hazard; moDC, monocyte-derived dendritic cell; IQR, interquartile range; FasL, Fas ligand.

⁴ G. Giaccone, C. Punt, Y. Ando, R. Ruÿter, N. Nishi, M. Peters, B. von Blomberg, R. Scheper, H. van der Vliet, A. van den Eertwegh, et al. A phase I study on the NKT cell ligand -galactosylceramide (KRN7000) in patients with solid tumors. Submitted for publication.

Received for publication September 20, 2001. Accepted for publication December 3, 2001.

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