Clonal expansion and decreased occurrence of peripheral blood gamma delta T cells of the V delta 2J delta 3 lineage in multiple sclerosis patients

Abstract Background: Recent data showed that gamma delta T cells can act as a vast functional setting of immune defense against tumors. Our previous study found that persist clonally expanded TRDV4 T cells might be relatively to better outcome for the patient with T-cell acute lymphoblastic leukemia (T-ALL) after hematopoietic stem cell transplantation (HSCT). However, little is known, the distribution and clonality of TRDV repertoire of gamma delta T cells in peripheral blood (PB) and its potential effect for clinical outcome in acute myeloid leukemia (AML) patients. Methods: Gamma delta T cells were sorted from peripheral blood of 30 patients with untreated de novo AML (AML-M0 6 cases, M1 1 case, M2 5 cases, M3 10 cases, M4 3 cases and M5 5 cases) and were observed the distribution of TRDV repertoire, while 12 healthy individuals served as normal controls. Then the TRDV repertoire were further analyzed by Genescan technique to determine the size of complementarity determining region 3 (CDR3) of TRDV (1-8) subfamilies genes and to evaluate the clonality of the detectable subfamilies of gamma delta cells. The binary Logistic regression analysis was used to explore the associations between clonal expansion of gamma delta T cells and outcome of AML patients. Results: The frequencies of TRDV1, TRDV3, TRDV4 and TRDV6 in gamma delta T cells from AML patients were significantly lower than that from healthy individuals (HI) (Figure A). The most frequently expanded TRDV subfamilies in AML patients were TRDV8 (56.67%) and TRDV4 (40%). Furthermore, the most frequently oligoclonally expanded TRDV subfamilies from AML patients were TRDV2 and TRDV4 subfamilies, and the clonal expansion frequencies were significant higher than that from healthy individuals, however, a significant lower clonal expansion frequency of TRDV1 was observed in AML patients (Figure B). Importantly, oligoclonalities of TRDV4 and TRDV8subfamilies were the independent protective factors for complete remission. In addition, the oligoclonal expansion frequencies of TRDV5 and TRDV6 subfamilies from the recurrence cases were significantly higher than that from non-recurrence cases. Significantly, oligoclonal TRDV5 and TRDV6subfamilies were found in the patients who developed AML relapse in different time point after first complete remission. Conclusions: The distribution and clonality of TRDV subfamilies significantly changed in gamma delta T cells from AML patients. Clonally expanded TRDV4 and TRDV8 T cells might contribute to immune response against AML, while oligoclonal TRDV5 and TRDV6 may be accompanied to patients who underwent AML relapse, the function of such oligoclones of gamma delta T cells is needed further investigation. Overall, these TRDV gamma delta T cell clones might be a potential immune biomarker for AML outcome. Foundation: This study was supported by grants from Natural Science Foundation of China (No.81200388), Natural Science Foundation of Guangdong Province (NO.2014A030313380) and the Project of the Zhujiang Science & Technology Star of Guangzhou City (No. 2013J2200046). Figure Figure. Disclosures No relevant conflicts of interest to declare.

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Transient increase in circulating gamma/delta T cells during Plasmodium vivax malarial paroxysms.

Journal of Experimental Medicine ◽

10.1084/jem.179.1.311 ◽

1994 ◽

Vol 179 (1) ◽

pp. 311-315 ◽

Cited By ~ 92

Author(s):

M K Perera ◽

R Carter ◽

R Goonewardene ◽

K N Mendis

Keyword(s):

T Cells ◽

Plasmodium Vivax ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Clinical Symptoms ◽

Gastrointestinal Symptoms ◽

Gamma Delta T Cells ◽

Gamma Delta ◽

Endemic Region ◽

Gastrointestinal Pathology

The percentage of peripheral blood mononuclear cells (PBMC) bearing the CD3+ phenotype and the alpha/beta and gamma/delta T cell receptors (TCR) in PBMC were examined in Plasmodium vivax malaria patients and convalescents. The cells were labeled with monoclonal antibodies, stained with either fluorescence or phycoerythrin, and examined by ultraviolet (UV) microscopy. A highly significant increase in both the proportion and the absolute numbers of gamma/delta T cells (p < 0.005 and < 0.001, respectively, Student's t test) was observed in nonimmune P. vivax patients during clinical paroxysms compared to nonmalarial controls. These T cells, which normally constitute not more than 3-5% of PBMC, constituted < or = to 30% of PBMC during paroxysms in these nonimmune patients in whom the clinical symptoms were severe. A less significant increase of gamma/delta T cells were also observed in these nonimmune patients during infection, between paroxysms and during convalescence. In contrast, in an age-matched group of semi-immune patients resident in a malaria-endemic region of the country, in whom the clinical disease was comparatively mild, there was no increase in gamma/delta T cells either during infection, even during paroxysms, or convalescence. The severity of disease symptoms in patients as measured by a clinical score correlated positively with the proportion of gamma/delta T cells in peripheral blood (r = 0.53, p < 0.01), the most significant correlation being found between the prevalence and severity of gastrointestinal symptoms, nausea, anorexia, and vomiting, and the proportion of gamma/delta T cells (r = 0.49, p = 0.002). These findings suggest that gamma/delta T cells have a role to play in the pathogenesis of malaria, possibly in the general constitutional disturbances and particularly in gastrointestinal pathology in malaria.

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Characterization of circulating gamma-delta T cells in relapsing vs remission multiple sclerosis

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2018.02.009 ◽

2018 ◽

Vol 318 ◽

pp. 65-71 ◽

Cited By ~ 6

Author(s):

Andreia Monteiro ◽

Catarina Cruto ◽

Pedro Rosado ◽

António Martinho ◽

Luiza Rosado ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Gamma Delta T Cells ◽

Gamma Delta

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Functional defects in peripheral blood T cells of multiple sclerosis patients

Journal of Neuroimmunology ◽

10.1016/0165-5728(94)90107-4 ◽

1994 ◽

Vol 52 (2) ◽

pp. 139-146 ◽

Cited By ~ 6

Author(s):

Martin H.G. Rep ◽

Rogier Q. Hintzen ◽

Chris H. Polman ◽

RenéA.W. van Lier

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Peripheral Blood ◽

Multiple Sclerosis Patients ◽

Functional Defects

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Role of .GAMMA./.DELTA. T-cells in the Peripheral Blood of Patients with Pulmonary Tuberculosis.

The Kurume Medical Journal ◽

10.2739/kurumemedj.48.175 ◽

2001 ◽

Vol 48 (2) ◽

pp. 175-181 ◽

Cited By ~ 1

Author(s):

NOBUKUNI YOSHIDA

Keyword(s):

T Cells ◽

Pulmonary Tuberculosis ◽

Peripheral Blood ◽

Gamma Delta T Cells ◽

Gamma Delta

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CD8+Foxp3+ T cells in peripheral blood of relapsing-remitting multiple sclerosis patients

Human Immunology ◽

10.1016/j.humimm.2010.01.024 ◽

2010 ◽

Vol 71 (5) ◽

pp. 437-441 ◽

Cited By ~ 25

Author(s):

Giovanni Frisullo ◽

Viviana Nociti ◽

Raffaele Iorio ◽

Domenico Plantone ◽

A. Katia Patanella ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Peripheral Blood ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Multiple Sclerosis Patients ◽

Relapsing Remitting Multiple Sclerosis

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Intracellular cytokine profile in T-cell subsets of multiple sclerosis patients: different features in primary progressive disease

Multiple Sclerosis Journal ◽

10.1177/135245850100700302 ◽

2001 ◽

Vol 7 (3) ◽

pp. 145-150 ◽

Cited By ~ 35

Author(s):

J Killestein ◽

B F Den Drijver ◽

W L Van der Graaff ◽

B MJ Uitdehaag ◽

C H Polman ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Peripheral Blood ◽

T Cell Subsets ◽

Primary Progressive ◽

Immunoregulatory Cytokines ◽

Immune Mediated ◽

Distinct Disease ◽

Circulating T Cells ◽

Multiple Sclerosis Patients

Objective: To evaluate the expression of cytokines in both CD4+ and CD8+ T cells derived from peripheral blood of untreated multiple sclerosis (MS) patients with either relapsing-remitting (RR), secondary progressive (SP) or primary progressive (PP) MS and healthy controls (HC). Background: MS is an immune-mediated disease and cytokines have been hypothesized to contribute significantly to disease progression. Compared to the relapse-onset (RR, SP) form of the disease, PPMS patients have different clinical, immunological and pathological features. Surprisingly, the ability of their circulating T cells to produce immunoregulatory cytokines has not been extensively studied so far. Methods: Seventy-two MS patients (24 RR, 26 SP, 22 PP) and 34 HC were studied. Stimulated peripheral blood derived CD4+ and CD8+ T cells were analyzed for IFN-g, IL-2, TNF-a, IL-4, IL-10 and IL-13 production. Results: MS patients express significantly more CD4+ and CD8+ T cells producing IFN-g compared to HC. Compared to the other forms of the disease, PPMS patients display a significant decrease in CD4+ T cells producing IL-2, IL-13 and TNF-a and a significant increase in CD8+ T cells producing IL-4 and IL-10. Conclusions: The data presented here demonstrate that patients with PPMS express less pro- and more anti-inflammatory cytokine producing T cells compared to the relapse-onset form of the disease, confirming the view on PPMS as a distinct disease entity.

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Constitutive expression of pore-forming protein in peripheral blood gamma/delta T cells: implication for their cytotoxic role in vivo.

Journal of Experimental Medicine ◽

10.1084/jem.172.6.1877 ◽

1990 ◽

Vol 172 (6) ◽

pp. 1877-1880 ◽

Cited By ~ 72

Author(s):

M Nakata ◽

M J Smyth ◽

Y Norihisa ◽

A Kawasaki ◽

Y Shinkai ◽

...

Keyword(s):

T Cells ◽

Cytotoxic Activity ◽

Peripheral Blood ◽

Human Peripheral Blood ◽

Constitutive Expression ◽

Immunocytochemical Staining ◽

Target Cells ◽

Gamma Delta T Cells ◽

Gamma Delta

The cytotoxic activity and pore-forming protein (PFP) expression of human peripheral blood (PB) gamma/delta T cells were examined. Fresh gamma/delta T cells isolated from PB lymphocytes by fluorescence-activated cell sorting exhibited a substantial natural killer-like cytotoxic activity against K562 target cells and had a high cytotoxic potential triggered by anti-CD3 monoclonal antibody (mAb) against P815 target cells bearing Fc gamma R. Immunocytochemical staining with an anti-PFP mAb revealed that virtually all PB gamma/delta T cells are granular lymphocytes with abundant PFP in their cytoplasmic granules. Constitutive expression of PFP in PB gamma/delta T cells was also demonstrated by Northern blot analysis. These observations support the proposed role of gamma/delta T cells in cytolytic immune surveillance in vivo.

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Dendritic Cells Can Be Primed to Concurrently Activate Both Unconventional Gamma/delta and Conventional alpha/beta T Cells.

Blood ◽

10.1182/blood.v108.11.3893.3893 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3893-3893

Author(s):

Francesca Fiore ◽

Barbara Castella ◽

Barbara Nuschak ◽

Raffaello Bertieri ◽

Sara Mariani ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Immune Responses ◽

Tumor Cells ◽

Peripheral Blood ◽

Adoptive Cell Therapy ◽

Effector Memory ◽

Gamma Delta T Cells ◽

Gamma Delta ◽

Alpha Beta

Abstract Vgamma9/Vdelta2 (gamma/delta) T cells represent the major subset of unconventional T cells circulating in the peripheral blood. Gamma/delta T cells play a major role in immune defenses against microbes, stressed cells and tumor cells. This property is based on their capability to naturally recognize phosphoantigens (pAgs), which are produced via the mevalonate (Mev) or the DOXP pathway in mammalian and nonmammalian cells, and induced self-ligands, which are de novo expressed or upregulated on the surface of stressed or tumor cells. Interestingly, gamma/delta T cells can also be activated by aminobisphosphonates (ABP)-treated monocytes. We have previously shown that ABP specifically target the Mev pathway of monocytes and induce the accumulation of phosphorylated Mev metabolites naturally recognized by gamma/delta T cells. The aim of this work was to determine whether ABP-treated dendritic cells (DC) can also activate gamma/delta T cells and whether this activation, if any, is detrimental or beneficial to the generation of antigen (Ag)-specific MHC-restricted immune responses mediated by conventional alpha/beta T cells. To this end, we have generated highly purified immature (iDC) and mature DC (mDC) from peripheral blood monocytes of healthy donors and incubated with zoledronic acid (Zol) for 24 hours. Zol is the most potent ABP currently available for clinical use. Zol treatment did not affect the phenotype and immunostimulatory properties of iDC and mDC. Zol-treated iDC and mDC induced a rapid and vigorous expansion of central memory and effector memory gamma/delta T cells. Zol-treated iDC were more potent inducers of gamma/delta T-cell activation than mDC and monocytes. Activated gamma/delta T cells displayed antitumor activity and expressed on the cell surface the appropriate antigen repertoire to target secondary lymphoid organs and exert costimulatory activity on conventional alpha/beta T cells. Indeed, an in vitro model showed that antigen-specific MHC-restricted immune responses againt the influenza matrix peptide were significantly improved by the concurrent activation of gamma/delta T cells. This is the first report showing that: 1) DC can simultaneously be primed to activate both gamma/delta and alpha/beta T cells; 2) the former act as cellular adjuvants for the development of adaptive immune responses. In conclusion, large numbers of gamma/delta T cells with effector and costimulatory activities can rapidly be generated by Zol-treated iDC/mDC. This strategy is worth of further investigation to improve adoptive cell therapy and vaccine interventions against tumors and infections.

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