Proinflammatory cytokines are associated with prolonged viral RNA shedding in COVID-19 patients.

Since December 2019, Coronavirus Disease 2019 (COVID-19) has emerged as a global pandemic. We aimed to investigate the clinical characteristics and analyzed the risk factors for prolonged viral RNA shedding. We retrospectively collected data from 112 hospitalized COVID-19 patients in a single center in Wuhan, China. Factors associated with prolonged viral RNA shedding (≥28 days) were investigated. Forty-nine (43.8%) patients had prolonged viral RNA shedding. Patients with prolonged viral shedding were older and had a higher rate of hypertension. Proinflammatory cytokines, including interleukin-2R (IL-2R) and tumor necrosis factor-α (TNF-α), were significantly elevated in patients with prolonged viral shedding. Multivariate analysis revealed that hypertension, older age, lymphopenia and elevated serum IL-2R were independent risk factors for prolonged viral shedding. This comprehensive investigation revealed the distinct characteristics between patients with or without prolonged viral RNA shedding. Hypertension, older age, lymphopenia and high levels of proinflammatory cytokines may be correlated with prolonged viral shedding.

Diagnosis of SARS-CoV-2 infection in the setting of the cytokine release syndrome.

INTRODUCTION: Coronavirus disease (COVID-19) can trigger a cytokine response storm (CRS) that is associated with high mortality but for which the underlying pathophysiology and diagnostics are not yet well characterized. This review provides an overview of the underlying immune profile of COVID-19-related CRS as well as laboratory markers for acute diagnosis and chronic follow-up of patients with SARS-CoV-2 and CRS. AREAS COVERED: Innate and acquired immune profiles in COVID-19-CRS, RNA-detection methods for SARS-CoV-2 in the setting of CRS including factors that affect assay performance, serology for SARS-CoV-2 in the setting of CRS, and other biomarkers for COVID-19 will be discussed. EXPERT OPINION: Studies support the implication of CRS in the pathogenesis, clinical severity and outcome of COVID-19 through the production of multiple inflammatory cytokines and chemokines from activated innate and adaptive immune cells. Although these inflammatory molecules, including IL-6, IL-2 R, IL-10, IP-10 and MCP-1, often correlate with disease severity as possible biomarkers, the pathogenic contributions of individual molecules and the therapeutic benefits of targeting them are yet to be demonstrated. Detection of SARS-CoV-2 RNA is the gold standard method for diagnosis of COVID-19 in the context of CRS but assay performance varies and is susceptible to false-negative results even as patients clinically deteriorate due to decreased viral shedding in the setting of CRS. Biomarkers including CRP, ferritin, D-dimer and procalcitonin may provide early clues about progression to CRS and help identify thrombotic and infectious complications of COVID-19.

Lymphoplasmacytic Lymphoma Presenting with Diarrhea and Joint Pain Which was Successfully Diagnosed by an MYD88 Mutation Analysis.

A 55-year-old man presented to our department with diarrhea, weight loss, fatigability, and polyarthralgia. Blood tests revealed elevated soluble interleukin-2 receptor levels and IgG-type M protein positivity, without any findings that were suggestive of collagen disease. After computed tomography (CT) detected enlarged lymph nodes in the abdominal para-aortic region, lymphoma was suspected. CT-guided needle biopsy of the lymph node did not help to achieve a definitive diagnosis; however, a bone marrow test showed the pathological features of B-cell lymphoma. A genetic examination detected a MYD88 L265P mutation; the mutation analysis was valuable in diagnosing lymphoplasmacytic lymphoma in a IgM-type M protein-negative patient.

Effect of tumor necrosis factor-induced protein 8 on T-cell-mediated immunity in mice after thermal injury.

Tumor necrosis factor-induced protein 8(TNFAIP8), the first identified member of the TNFAIP8 family, shares considerable sequence homology with members of this family. It is expressed in a wide variety of human normal tissues, with relatively higher levels in lymphoid tissues and placenta. The present study was designed to examine the effect of TNFAIP8 on T-cell-mediated immunity secondary to burn injury. Sixty male mice were randomly divided into four groups as follows: sham burn group, burn group, burn with TNFAIP8-siRNA transfection group, and burn with negative control transfection group, and they were sacrificed at designated time points. CD4+ T cells were isolated using MACS microbeads. T-Cell proliferation was analyzed with MTT assay, and IL-2, soluble IL-2R, IL-4, interferon-γ (IFN-γ) were determined with enzyme-linked immunosorbent assay kits. It was found that CD4+ T lymphocyte proliferative activity was significantly down-regulated when TNFAIP8 gene was silenced by siRNA in mice at 24 h post burn. Down-regulation of TNFAIP8 can significantly decrease expression levels of IL-2 and soluble IL-2R at 24 h after thermal injury. These results demonstrated that TNFAIP8 appeared to be involved in the immune regulation of CD4+ T lymphocytes, and the decreased expression of TNFAIP8 could affect T lymphocyte functions after thermal injury.

Signal transduction in primary human T lymphocytes in altered gravity during parabolic flight and clinostat experiments.

BACKGROUND/AIMS: Several limiting factors for human health and performance in microgravity have been clearly identified arising from the immune system, and substantial research activities are required in order to provide the basic information for appropriate integrated risk management. The gravity-sensitive nature of cells of the immune system renders them an ideal biological model in search for general gravity-sensitive mechanisms and to understand how the architecture and function of human cells is related to the gravitational force and therefore adapted to life on Earth. METHODS: We investigated the influence of altered gravity in parabolic flight and 2D clinostat experiments on key proteins of activation and signaling in primary T lymphocytes. We quantified components of the signaling cascade 1.) in non-activated T lymphocytes to assess the "basal status" of the cascade and 2.) in the process of activation to assess the signal transduction. RESULTS: We found a rapid decrease of CD3 and IL-2R surface expression and reduced p-LAT after 20 seconds of altered gravity in non-activated primary T lymphocytes during parabolic flight. Furthermore, we observed decreased CD3 surface expression, reduced ZAP-70 abundance and increased histone H3-acetylation in activated T lymphocytes after 5 minutes of clinorotation and a transient downregulation of CD3 and stable downregulation of IL-2R during 60 minutes of clinorotation. CONCLUSION: CD3 and IL-2R are downregulated in primary T lymphocytes in altered gravity. We assume that a gravity condition around 1g is required for the expression of key surface receptors and appropriate regulation of signal molecules in T lymphocytes.

Dengue virus serotype-2 impairs proliferation of healthy donors' T lymphocytes.

OBJECTIVES: T lymphocytes are not infected by dengue virus (DENV), nevertheless it is possible that exposure to DENV may affect their function. T lymphocytes from DENV-infected individuals are impaired in their proliferative capacity, although this effect has been attributed to altered function of antigen-presenting cells rather than to an intrinsic defect on T lymphocytes. Here we analyzed whether T lymphocytes from healthy donors became impaired in their proliferative capacity following in vitro exposure to DENV serotype-2 (DENV-2), as well as the possible mechanisms for this. METHODS: Isolated CD4+ and CD8+ T lymphocytes from healthy donors were in vitro exposed to DENV-2, before polyclonal activation, cell proliferation, IL-2 synthesis. IL-2Rα expression, nuclear translocation of NF-AT and NF-κB, and intracellular calcium flux were assessed. RESULTS: In vitro exposure of both CD4+ and CD8+ T lymphocytes from healthy donors to DENV-2 impairs cell proliferation, IL-2 synthesis, and IL-2Rα (CD25) cell membrane expression. Signalling wise, exposure to DENV-2 impairs the nuclear translocation of NF-AT, downstream of intracellular calcium mobilization, as well as that of NF-κB. CONCLUSION: In the course of a dengue infection, direct exposure of T lymphocytes to DENV could affect cell-mediated immune responses.

HIV infection deregulates the balance between regulatory T cells and IL-2-producing CD4 T cells by decreasing the expression of the IL-2 receptor in Treg.

Indexation of regulatory T cells (Treg) to the number of activated T cells constitutes a homeostatic mechanism ensuring that T-cell expansion remains under control. However, immune hyperactivation observed in HIV-infected patients suggests a possible dysfunction of this mechanism. Here we show that the Treg/IL-2-producing cells' balance is deeply disturbed in viremic HIV-infected patients. We found a lower expression of IL-2 receptor alpha on Treg from viremic patients. We confirmed in vitro that HIV infection of Treg downregulates IL-2 receptor alpha and phosphorylated STAT5. Our results argue for an impaired capacity of Treg to sense the expansion of activated T cells in HIV-infected patients that could contribute to the immune deregulation.

Human complement C3 deficiency: Th1 induction requires T cell-derived complement C3a and CD46 activation.

Human T helper type 1 (Th1) responses are essential in defense. Although T cell receptor (TCR) and co-stimulator engagement are indispensable for T cell activation, stimulation of additional receptor pathways are also necessary for effector induction. For example, engagement of the complement regulator CD46 by its ligand C3b generated upon TCR activation is required for IFN-γ production as CD46-deficient patients lack Th1 responses. Utilizing T cells from two C3-deficient patients we demonstrate here that normal Th1 responses also depend on signals mediated by the anaphylatoxin C3a receptor (C3aR). Importantly, and like in CD46-deficient patients, whilst Th1 induction are impaired in C3-deficient patients in vitro, their Th2 responses are unaffected. Furthermore, C3-deficient CD4(+) T cells present with reduced expression of CD25 and CD122, further substantiating the growing notion that complement fragments regulate interleukin-2 receptor (IL-2R) assembly and that disturbance of complement-guided IL-2R assembly contributes to aberrant Th1 effector responses. Lastly, sustained intrinsic production of complement fragments may participate in the Th1 contraction phase as both C3a and CD46 engagement regulate IL-10 co-expression in Th1 cells. These data suggest that C3aR and CD46 activation via intrinsic generation of their respective ligands is an integral part of human Th1 (but not Th2) immunity.

Augmented adenovirus transduction of murine T lymphocytes utilizing a bi-specific protein targeting murine interleukin 2 receptor.

Adenoviruses are currently used in a variety of bench and bedside applications. However, their employment in gene delivery to lymphocyte lineages is hampered by the lack of coxsackie virus and adenovirus receptor (CAR) on the cell surface. Exploitation of an alternative receptor on the surface of T lymphocytes can allow for utilization of adenovirus in a variety of T lymphocyte-based diseases and therapies. Here, we describe how resistance to infection can be overcome by the utilization of a bi-specific fusion protein, soluble CAR murine interleukin 2 (sCAR-mIL-2), that retargets adenovirus to the murine IL-2 receptor (IL-2R). Infection of a murine T-cell line, CTLL-2, with a sCAR-mIL-2/Adenovirus conjugate provided a ninefold increase in both green fluorescence protein-positive cells and luciferase expression. In addition, this increase in infection was also seen in isolated primary murine T lymphocytes. In this context, the sCAR-mIL-2 adapter provided a fourfold gene transduction increase in activated primary murine T lymphocytes. Our results show that recombinant sCAR-mIL-2 fusion protein promotes IL-2R-targeted gene transfer to murine T lymphocytes and that alternative targeting can abrogate their native resistance to infection.

Postthymic expansion in human CD4 naive T cells defined by expression of functional high-affinity IL-2 receptors.

As the thymus involutes with age, the maintenance of peripheral naive T cells in humans becomes strongly dependent on peripheral cell division. However, mechanisms that orchestrate homeostatic division remain unclear. In this study we present evidence that the frequency of naive CD4 T cells that express CD25 (IL-2 receptor α-chain) increases with age on subsets of both CD31(+) and CD31(-) naive CD4 T cells. Analyses of TCR excision circles from sorted subsets indicate that CD25(+) naive CD4 T cells have undergone more rounds of homeostatic proliferation than their CD25(-) counterparts in both the CD31(+) and CD31(-) subsets, indicating that CD25 is a marker of naive CD4 T cells that have preferentially responded to survival signals from self-Ags or cytokines. CD25 expression on CD25(-) naive CD4 T cells can be induced by IL-7 in vitro in the absence of TCR activation. Although CD25(+) naive T cells respond to lower concentrations of IL-2 as compared with their CD25(-) counterparts, IL-2 responsiveness is further increased in CD31(-) naive T cells by their expression of the signaling IL-2 receptor ß-chain CD122, forming with common γ-chain functional high-affinity IL-2 receptors. CD25 plays a role during activation: CD25(+) naive T cells stimulated in an APC-dependent manner were shown to produce increased levels of IL-2 as compared with their CD25(-) counterparts. This study establishes CD25(+) naive CD4 T cells, which are further delineated by CD31 expression, as a major functionally distinct immune cell subset in humans that warrants further characterization in health and disease.

All subunits of the interleukin-2 receptor are expressed by canine cutaneous mast cell tumours.

Cutaneous mast cell tumours (MCTs) are among the most important skin tumours in dogs. Apart from c-KIT mutations, which are present in <18% of MCTs, little is known of the mechanisms of MCT development and independent growth of tumour cells. Recently, the α-subunit (CD25) of the interleukin (IL)-2 receptor (IL-2R) has been found to be expressed by canine cutaneous MCTs and this expression is negatively correlated with tumour grade. We thus hypothesized that the other two subunits of the IL-2R and the ligand IL-2 are also expressed and that IL-2-dependent pathways may have an impact on MCT development and independent tumour cell growth. Messenger RNA and protein expression levels of the IL-2R ß-subunit (CD122), the IL-2R γ-subunit (CD132) and IL-2 were analyzed in canine cutaneous MCTs and compared with tumour grade and c-KIT mutation status. Eighty-six percent of the tumours expressed both subunits of the IL-2R and 64% expressed IL-2. In addition, neoplastic mast cells seem able to bind IL-2. IL-2Rγ and IL-2 protein expression levels were significantly decreased in higher grade tumours and IL-2 expression was significantly decreased in c-KIT mutated tumours. Thus, expression of the complete IL-2R and its ligand by canine cutaneous MCTs indicates a potential impact of IL-2R signalling in MCT development and tumour cell proliferation. The decrease in IL-2R expression with increasing histological evidence of malignancy suggests that the IL-2R may be more relevant for early MCT development and well-differentiated tumours.

Pesticide induced marrow toxicity and effects on marrow cell population and on hematopoietic stroma.

Long term inhalation of toxic pesticides used for the domestic and industrial purposes have been shown to cause moderate to severe hematotoxicity and increased incidence of several marrow degenerative diseases, specifically hypoplastic bone marrow failure condition in humans. The progression of pesticide induced hematotoxicity and the exact underlying mechanisms of toxicity that play major role in limiting normal hematopoiesis are not quite well explained. In this present study, we have developed an animal model of hypoplastic bone marrow failure following pesticide exposure to show the deleterious effects of toxic pesticides on mouse hematopoietic system. Here we have presented the results of studying long-term marrow explant culture, IL-2, IL-3 and IL-5 receptors expression profile, fibroblast colony forming unit (CFU-F), hematopoietic progenitor cell colony formation and caspase-3 expression by the bone marrow cells. We have also identified the expression levels of several extracellular apoptosis markers (CD95/Fas) and intracellular apoptosis inducer proteins (pASK1, pJNK, caspase-3 and cleaved caspase-3) in the bone marrow cells of pesticide exposed mice. The long-term marrow explant culture demonstrated the impairment in proliferation of the stromal cells/stromal fibroblasts in culture. Decreased IL-2, IL-3 and IL-5 receptors expression profile essentially hinted at the suppressed cytokine activity in the pesticide exposed marrow. CFU-F analysis showed the defect in functional maturation of the stromal fibroblasts. The decreased hematopoietic progenitor cell colony formation indicated the toxicity induced inhibition of cellular proliferation and functional maturation of hematopoietic stem/progenitor cells in pesticide exposed marrow. We have detected a sharp increase in the expression levels of both the extracellular Fas-antigen and intracellular apoptosis inducer proteins in the bone marrow cells of pesticide exposed mice that explained well, the apoptosis pathway involved following marrow toxicity. The decreased proliferation and functional maturation of marrow stromal cells and hematopoietic progenitors with subsequent increase in marrow cellular apoptosis following pesticide toxicity provided the base necessary for explaining the increased incidence of hypoplastic bone marrow failure in humans exposed to moderate to high concentrations of pesticides.

Cutting edge: a novel mechanism bridging innate and adaptive immunity: IL-12 induction of CD25 to form high-affinity IL-2 receptors on NK cells.

NK cell expression and use of the IL-2Rα-chain (CD25), required for the high-affinity IL-2R, remain poorly understood. The studies reported in this article demonstrate that infections with murine CMV (MCMV), but not with lymphocytic choriomeningitis virus, induce CD25 on NK cells, along with high levels of IL-12 and IL-18. The cytokines act ex vivo to increase CD25 levels, and IL-12, IL-12R, and STAT4, but not the NK activating receptor Ly49H, are required for peak induction in vivo. All examined NK cell populations are driven into proliferation and incorporate BrdU in response to high ex vivo concentrations of IL-2, but only those from MCMV infection respond to low ex vivo concentrations of IL-2. The numbers of NK cells elicited during MCMV infection are reduced by IL-2 neutralization. Thus, a link between innate and adaptive immunity is established by which composition of innate cytokine responses sets up to promote NK cell use of a factor supporting adaptive responses.

Long-term complications, immunologic effects, and role of passage for outcome in mesenchymal stromal cell therapy.

Thirty-one patients treated with mesenchymal stromal cells (MSCs) for acute graft-versus-host disease (aGVHD) or hemorrhagic cystitis between 2002 and 2007 were followed to investigate predictors of outcome, immunologic effects in vivo, and long-term survival. There was no correlation between in vitro suppression by MSCs in mixed lymphocyte cultures and outcome. Soluble IL-2 receptors were measured in blood before and after MSC infusion and declined significantly during the first week after MSC infusion (P = .03). Levels of interleukin-6 and HLA-G were unaffected. Infectious complications occurred several years after recovery from aGVHD. Cytomegalovirus viral load was high, and cytomegalovirus disease was common. Among patients recovering from aGVHD, 54% died of late infections, between 4 months and 2 years after MSC treatment. No increase in leukemia relapse or graft rejection was found. Children had a better survival rate than adults (P = .005). In GVHD patients, 1-year survival was 75% in patients who received early-passage MSCs (from passages 1-2) in contrast to 21% using later passage MSCs (from passages 3-4) (P < .01). We conclude that treatment with early-passage MSCs improved survival in patients with therapy-resistant GVHD. Death from infection was common in MSC-treated patients, but there was no increase in leukemia relapse.

[The use of cytoflavin in combined neurometabolic therapy of acute cerebral insufficiency associated with acute poisoning with neurotropic poisons].

Examination and treatment of 262 patients with severe acute intoxication by neurotropic poisons and unaffected oxygen delivery system showed that inclusion of cytoflavin in combined neurometabolic therapy of acute cerebral insufficiency significantly reduced severity of metabolic disorders. Specifically, tissue hypoxy, endotoxicosis, lipid peroxidation activity, and immunosuppression decreased while antioxidative protection and clinical picture were improved. Duration of comatose state and artificial lung ventilation was reduced from 64.5 +/- 15.1 to 28.8 +/- 10.2 hours and that of critical condition from 117.2 +/- 17.2 to 63.7 +/- 9.2 hours. Overall lethality dropped from 16 to 9.9%.

Effects of 5-FU on DNA synthesis and cytotoxicity of human lymphocytes induced by IL-2, TGF-beta3 and PGE2.

BACKGROUND: Low 5-fluorouracil (5-FU) concentrations cause a significant increase in DNA synthesis in mitogen-activated human lymphocytes. MATERIALS AND METHODS: We explored 2.5 microM 5-FU-induced DNA synthesis by testing 5-FU activity in hypoxanthine-aminopterin-thymidine (HAT)-containing medium, and its effect on thymidylate synthase (TS) activity and CD25 expression in interleukin (IL)-2-activated human peripheral blood mononuclear cells (PBMCs) and the combined effects with prostaglandin E(2) (PGE(2)) and transforming growth factor (TGF)-beta3. RESULTS: The co-stimulatory effect of 2.5 microM 5-FU on DNA synthesis was abrogated in HAT-cultured medium. 5-FU substantially reduced TS activity by 50% in IL-2-activated PBMCs. 5-FU combined with TGF-beta3 and PGE(2) did not alter their inhibitory effects on IL-2-activated natural killer cell cytotoxicity, but substantially affected increased DNA synthesis of cells cultured in IL-2 and co-cultured with 10 ng/ml TGF-beta3 and 10 microM PGE(2). CONCLUSION: Low 5-FU concentrations increase DNA synthesis in lymphocytes and exert a co-stimulatory activity on TGF-beta3 and PGE(2) modulation of IL-2-activated lymphocytes.

WIP is critical for T cell responsiveness to IL-2.

The Wiskott-Aldrich syndrome (WAS) interacting protein (WIP) stabilizes the WAS protein (WASP), the product of the gene mutated in WAS. WIP-deficient T cells have low WASP levels, limiting the usefulness of WIP KO mice in defining the role of WIP in T cell function. To define this role, we compared WIP/WASP double KO (DKO) mice to WASP KO mice on DO11.10 background. T cell development was normal in both strains, but peripheral T cell numbers were significantly decreased in DKO mice. WASP KO T cells proliferated and secreted IL-2 normally in response to OVA peptide (OVAp). In contrast, T cells from DKO mice proliferated poorly in response to OVAp in vitro, and cutaneous hapten hypersensitivity was deficient in these mice. DKO T cells up-regulated CD25 expression and secreted normal amounts of IL-2 after antigen stimulation, but had defective response to IL-2, evidenced by failure to further up-regulate CD25 expression, phosphorylate STAT5, and induce expression of STAT5-dependent genes. DKO, but not WASP KO, T cells had a disrupted subcortical actin cytoskeleton and impaired actin polymerization after T cell antigen receptor (TCR) ligation. These results indicate that WIP is essential for IL-2 signaling and responsiveness in T cells, possibly because of its critical role in TCR-triggered actin cytoskeletal reorganization.

[Preparation of fractions and characteristic of neutrophilokines complex induced by Yersinia pestis EV].

Biochemical and immunobiologic characteristics of fractions of neutrophilokines during primary and secondary immune response against plague infection are presented. Fractions were obtained using gel chromatography from neutrophilokines complex induced by vaccine strain of Yersinia pestis. It was revealed that fractions of neutrophilokines regulate IL-2 synthesis by Th1-helpers, IL-4 and IL-5 synthesis by Th2-helpers and also expression of IL-2 receptors by immunocompetent cells. Helper effect of neutrophilokines' fractions was more pronounced during secondary immune response.

Changes of immunological parameters reflect quality of life-related toxicity during chemotherapy in patients with advanced colorectal cancer.

UNLABELLED: Anticancer drugs may frequently induce host immunosuppression and symptomatic toxicities. Once symptomatic toxicity occurs, the patient's quality-of-life (QOL) is reduced. Since little is known of the relationship between host immunity and the toxicity of chemotherapy, the host immunity before and after chemotherapy was compared to assess whether it is related to symptomatic toxicity during chemotherapy. PATIENTS AND METHODS: Fourteen patients with colorectal cancer underwent leucovorin /5-fluorouracil (LV/5-FU) treatment, or S-1/irinotecan (CPT-11). Host immunity (cytokine production of peripheral blood mononuclear cell (PBMC), serum soluble interleukin-2 receptor (sIL-2R) levels and phenotypic analyses of PBMC were measured before and after the first chemotherapy. RESULTS: An increase of sIL-2R, CD4+CD25+ T-cells and the CD4/8 ratio in patients with symptomatic adverse reactions were found. These changes in the first chemotherapy were significantly different (p = 0.0211, p = 0.0087, p = 0.0234). CONCLUSION: The current study indicated that there are some parameters correlated with toxicity during chemotherapy which effect QOL. In such patients, negative influences on host immunity, such as an increase of sIL-2R and regulatory T-cells, and a decrease of cytotoxic T-cells could occur.

Activation of cytotoxic T-cell receptor gammadelta T lymphocytes in response to specific stimulation in myelodysplastic syndromes.

BACKGROUND: We previously reported that the function and proliferation of natural killer cells in myelodysplastic syndromes are defective. T-cell receptor gammadelta T cells are other important components of innate immunity that have been recently implicated in the immune response against hematologic malignancies. DESIGN AND METHODS: We evaluated the phenotype, function, and in vitro expansion of myelodysplastic syndrome patient-derived gammadelta T cells in response to interleukin-2 and bromohalohydrin pyrophosphate, a synthetic phosphoantigen with a potent T-cell receptor gammadelta agonist effect that specifically activates and amplifies this T-cell population. RESULTS: Vgamma9Vdelta2 T cells, the major circulating gammadelta T-cell subset, were reduced in myelodysplastic syndromes, but mainly in myelodysplastic syndromes' patients with associated autoimmune diseases, suggesting that this anomaly was largely due to the autoimmune component. On the other hand, bromohalohydrin pyrophosphate-induced expansion of the Vgamma9Vdelta2 T-cell population in all 15 control samples, but in only 26 of 43 (60%) myelodysplastic syndromes patients. The response to bromohalohydrin pyrophosphate was independent of World Health Organization subtype, cytogenetic findings and International Prognostic Scoring System score. In responding myelodysplastic syndromes patients, expanded Vgamma 9Vdelta2 T cells exhibited normal cytolytic and secretory activity against leukemic and myelodysplastic syndromes cell lines; fluorescence in situ hybridization analysis indicated that these Vgamma 9Vdelta2 T cells were not derived from the myelodysplastic syndromes clone. However, these Vgamma 9Vdelta2 T cells from the MDS patients had limited proliferative capacity in response to interleukin-2 despite having normal expression of interleukin-2 receptor chains (alpha beta gamma ). CONCLUSIONS: These results, combined with our previous findings concerning natural killer cells, suggest that there are immune surveillance defects in myelodysplastic syndromes, which may contribute to the pathogenesis of these syndromes.