Immunosenescence: participation of T lymphocytes and myeloid-derived suppressor cells in aging-related immune response changes

Taenia crassicepsis a cestode parasite of rodents (in its larval stage) and canids (in its adult stage) that can also parasitize immunocompromised humans. We have studied the immune response elicited by this helminth and its antigens in mice and human cells, and have discovered that they have a strong capacity to induce chronic Th2-type responses that are primarily characterized by high levels of Th2 cytokines, low proliferative responses in lymphocytes, an immature and LPS-tolerogenic profile in dendritic cells, the recruitment of myeloid-derived suppressor cells and, specially, alternatively activated macrophages. We also have utilized the immunoregulatory capabilities of this helminth to successfully modulate autoimmune responses and the outcome of other infectious diseases. In the present paper, we review the work of others and ourselves with regard to the immune response induced byT. crassicepsand its antigens, and we compare the advances in our understanding of this parasitic infection model with the knowledge that has been obtained from other selected models.

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Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19)

Cell Death and Differentiation ◽

10.1038/s41418-020-0572-6 ◽

2020 ◽

Vol 27 (11) ◽

pp. 3196-3207 ◽

Cited By ~ 19

Author(s):

Chiara Agrati ◽

Alessandra Sacchi ◽

Veronica Bordoni ◽

Eleonora Cimini ◽

Stefania Notari ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Mononuclear Cells ◽

Severe Disease ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Cell Functions ◽

Convalescent Phase

Abstract SARS-CoV-2 is associated with a 3.4% mortality rate in patients with severe disease. The pathogenesis of severe cases remains unknown. We performed an in-depth prospective analysis of immune and inflammation markers in two patients with severe COVID-19 disease from presentation to convalescence. Peripheral blood from 18 SARS-CoV-2-infected patients, 9 with severe and 9 with mild COVID-19 disease, was obtained at admission and analyzed for T-cell activation profile, myeloid-derived suppressor cells (MDSCs) and cytokine profiles. MDSC functionality was tested in vitro. In four severe and in four mild patients, a longitudinal analysis was performed daily from the day of admission to the early convalescent phase. Early after admission severe patients showed neutrophilia, lymphopenia, increase in effector T cells, a persisting higher expression of CD95 on T cells, higher serum concentration of IL-6 and TGF-β, and a cytotoxic profile of NK and T cells compared with mild patients, suggesting a highly engaged immune response. Massive expansion of MDSCs was observed, up to 90% of total circulating mononuclear cells in patients with severe disease, and up to 25% in the patients with mild disease; the frequency decreasing with recovery. MDSCs suppressed T-cell functions, dampening excessive immune response. MDSCs decline at convalescent phase was associated to a reduction in TGF-β and to an increase of inflammatory cytokines in plasma samples. Substantial expansion of suppressor cells is seen in patients with severe COVID-19. Further studies are required to define their roles in reducing the excessive activation/inflammation, protection, influencing disease progression, potential to serve as biomarkers of disease severity, and new targets for immune and host-directed therapeutic approaches.

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Myeloid-Derived Suppressor Cells Increase in Chronic Myeloid Leukemia and Exert Immune Suppressive Activity.

Blood ◽

10.1182/blood.v120.21.2779.2779 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2779-2779

Author(s):

Cesarina Giallongo ◽

Nunziatina Parrinello ◽

Daniele Tibullo ◽

Piera La Cava ◽

Alessandra Cupri ◽

...

Keyword(s):

T Cell ◽

Chronic Myeloid Leukemia ◽

T Lymphocytes ◽

Enzymatic Activity ◽

Myeloid Leukemia ◽

Myeloid Cells ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Arginase 1

Abstract Abstract 2779 Background: Tumor cells are able to develop immune evasion mechanisms which induce a state of immune tolerance and inactivate tumor-specific T cells. In this context, in some solid tumors it has been demonstrated that a subpopulation of myeloid cells, defined as “myeloid-derived suppressor cells” (MDSCs), plays an important role in inducing T cell tolerance by production of arginase that depletes microenvironment of arginine, an essential aminoacid for T cell function. Since chronic myeloid leukemia (CML) patients have high levels of immature myeloid cells it is of interest to investigate if these cells have MDSCs phenotype and activity. Aim: The aim of this study was to analyze MDSCs and investigate their involvement in T-cell anergy of CML patients. Methods: MDSCs were analyzed in peripheral blood (PB) of 13 CML patients (at diagnosis and during therapy) and healthy donors (HD; n=20) by cytofluorimetric analysis (CD14+DR- for monocytic MDSCs and CD11b+CD33+CD14-DR- for granulocytic MDSCs). Arginase 1 expression was assessed in PB of HD and CML patient using real time PCR. Purification of granulocytes, monocytes and lymphocytes from PB was performed by a positive magnetic separation kit (EasySep, STEMCELL Technologies). Arginase activity was measured in granulocyte lysates using a colorimetric test after enzymatic activation and arginine hydrolysis. To evaluate the activation of CD3+ T lymphocytes after incubation with phytoemagglutinin, we analyzed at 24, 48, 72 h the following markers: CD69+, CD71+, DR+. Microvesicles were isolated from CML serum at diagnosis (n=5) by sequential ultracentrifugation. Results: CML patients showed high levels of monocytic and granulocytic MDSCs at diagnosis in comparison to HD (63±8 and 83±12,2% respectively in CML vs 4,9±2,1 and 55,8±5,3% respectively in HD; p<0.001) while after 3–6 months of tyrosine kinase inhibitors (TKIs) therapy MDSC levels returned to normal values. Either in PB and in the purified granulocytes subpopulation, arginase1 expression showed a 30 fold increase in CML at diagnosis (CML vs HD: p<0.01) and decreased after therapy. We also evaluated arginase enzymatic activity in granulocytes and we found it increased in CML patients (n=4) compared to HD (n=5) (p<0.05). CML as well as HD T lymphocytes showed a normal activation in vitro which was significantly lost when they was incubated with CML serum (n=4). In addition, an increase of monocytic MDSCs in vitro was observed after incubation of HD monocytes with CML serum (39±6%; p<0.01) or microvescicles (9,2±1,2%; p<0.05) compared to control serum. Conclusions: Granulocytic and monocytic MDSCs are increased in CML patients at diagnosis and decrease during TKIs treatment. Their levels also correlates with Arginase 1 expression and enzymatic activity in granulocytes. CML serum as well as CML microvesicles increase the percentage of HD monocytic MDSCs. Moreover, CML serum leads to anergy of T lymphocytes, probably by Arginase 1 secretion. Disclosures: Off Label Use: Eltrombopag is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP).

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Upregulation of CD3ζ and L‐selectin in antigen‐specific cytotoxic T lymphocytes by eliminating myeloid‐derived suppressor cells with doxorubicin to improve killing efficacy of neuroblastoma cells in vitro

Journal of Clinical Laboratory Analysis ◽

10.1002/jcla.24158 ◽

2021 ◽

Author(s):

Weili Xu ◽

Suolin Li ◽

Meng Li ◽

Hui Zhou ◽

Xiaofeng Yang

Keyword(s):

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Neuroblastoma Cells ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells

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Circulating Immune Biomarkers in Peripheral Blood Correlate With Clinical Outcomes in Advanced Breast Cancer

10.21203/rs.3.rs-228062/v1 ◽

2021 ◽

Author(s):

Natalia Palazón-Carrión ◽

Carlos Jiménez-Cortegana ◽

M. Luisa Sánchez-León ◽

Fernando Henao-Carrasco ◽

Esteban Nogales-Fernández ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

T Lymphocytes ◽

Regulatory T Cells ◽

Advanced Breast Cancer ◽

Peripheral Blood ◽

Clinical Benefit ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Immune Biomarkers

Abstract Identification of the different elements intervening at the immunoedition process, in each body compartment, seems key to explain clinical evolution in several tumor types. In this study, a set of immune biomarkers (myeloid derived suppressor cells, regulatory T cells, and OX40+ and PD-1+ T lymphocytes counts) in peripheral blood of patients diagnosed with advanced breast cancer, were analyzed prior to and along the implementation of first line antineoplastic therapy. Subsequently, a formal comparison between groups with clinical benefit versus progression of disease and with a healthy women cohort was executed. Results reflected that patients basally showed higher levels of myeloid derived suppressor cells (35.43, IR=180.73 vs 17.53, IR=16.96 cells/μl; p=0.001) and regulatory T cells (32.05, IR=29.84 vs 22.61, IR=13.57 cells/μl; p=0.001) in comparison with healthy women. Furthermore, after therapy, an increase in the number of activated T lymphocytes (expressing OX40), and a decrease of immune inhibitory cells (MDSCs, and Tregs), and the number of inhibited (or exhausted) T lymphocytes (expressing PD-1), could be ascertained in patients with clinical benefit (p≤0.001). The opposite trend was observed in the case of disease progression. These findings suggest that some critical immune elements can be easily detected and measured in peripheral blood, which open a new opportunity for translational research, as they seem to be clearly correlated with clinical evolution, at least in ABC.

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Calcium/Calmodulin Dependent Protein Kinase Kinase 2 Regulates the Expansion of Tumor-Induced Myeloid-Derived Suppressor Cells

Frontiers in Immunology ◽

10.3389/fimmu.2021.754083 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wei Huang ◽

Yaping Liu ◽

Anthony Luz ◽

Mark Berrong ◽

Joel N. Meyer ◽

...

Keyword(s):

Immune Response ◽

Protein Kinase ◽

Bone Marrow Cells ◽

Suppressor Cells ◽

Cell Types ◽

T Cell Response ◽

Tumor Rejection ◽

Myeloid Derived Suppressor Cells ◽

Calcium Calmodulin Dependent

Myeloid-derived suppressor cells (MDSCs) are a hetero geneous group of cells, which can suppress the immune response, promote tumor progression and impair the efficacy of immunotherapies. Consequently, the pharmacological targeting of MDSC is emerging as a new immunotherapeutic strategy to stimulate the natural anti-tumor immune response and potentiate the efficacy of immunotherapies. Herein, we leveraged genetically modified models and a small molecule inhibitor to validate Calcium-Calmodulin Kinase Kinase 2 (CaMKK2) as a druggable target to control MDSC accumulation in tumor-bearing mice. The results indicated that deletion of CaMKK2 in the host attenuated the growth of engrafted tumor cells, and this phenomenon was associated with increased antitumor T cell response and decreased accumulation of MDSC. The adoptive transfer of MDSC was sufficient to restore the ability of the tumor to grow in Camkk2-/- mice, confirming the key role of MDSC in the mechanism of tumor rejection. In vitro studies indicated that blocking of CaMKK2 is sufficient to impair the yield of MDSC. Surprisingly, MDSC generated from Camkk2-/- bone marrow cells also showed a higher ability to terminally differentiate toward more immunogenic cell types (e.g inflammatory macrophages and dendritic cells) compared to wild type (WT). Higher intracellular levels of reactive oxygen species (ROS) accumulated in Camkk2-/- MDSC, increasing their susceptibility to apoptosis and promoting their terminal differentiation toward more mature myeloid cells. Mechanistic studies indicated that AMP-activated protein kinase (AMPK), which is a known CaMKK2 proximal target controlling the oxidative stress response, fine-tunes ROS accumulation in MDSC. Accordingly, failure to activate the CaMKK2-AMPK axis can account for the elevated ROS levels in Camkk2-/- MDSC. These results highlight CaMKK2 as an important regulator of the MDSC lifecycle, identifying this kinase as a new druggable target to restrain MDSC expansion and enhance the efficacy of anti-tumor immunotherapy.

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Reduced Expression of Autophagy Markers and Expansion of Myeloid-Derived Suppressor Cells Correlate With Poor T Cell Response in Severe COVID-19 Patients

Frontiers in Immunology ◽

10.3389/fimmu.2021.614599 ◽

2021 ◽

Vol 12 ◽

Cited By ~ 1

Author(s):

Sergej Tomić ◽

Jelena Đokić ◽

Dejan Stevanović ◽

Nataša Ilić ◽

Alisa Gruden-Movsesijan ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

B Cells ◽

Cell Response ◽

Suppressor Cells ◽

T Cell Response ◽

T Cell Subsets ◽

Myeloid Derived Suppressor Cells ◽

Immunological Mechanisms

Widespread coronavirus disease (COVID)-19 is causing pneumonia, respiratory and multiorgan failure in susceptible individuals. Dysregulated immune response marks severe COVID-19, but the immunological mechanisms driving COVID-19 pathogenesis are still largely unknown, which is hampering the development of efficient treatments. Here we analyzed ~140 parameters of cellular and humoral immune response in peripheral blood of 41 COVID-19 patients and 16 age/gender-matched healthy donors by flow-cytometry, quantitative PCR, western blot and ELISA, followed by integrated correlation analyses with ~30 common clinical and laboratory parameters. We found that lymphocytopenia in severe COVID-19 patients (n=20) strongly affects T, NK and NKT cells, but not B cells and antibody production. Unlike increased activation of ICOS-1+ CD4+ T cells in mild COVID-19 patients (n=21), T cells in severe patients showed impaired activation, low IFN-γ production and high functional exhaustion, which correlated with significantly down-regulated HLA-DR expression in monocytes, dendritic cells and B cells. The latter phenomenon was followed by lower interferon responsive factor (IRF)-8 and autophagy-related genes expressions, and the expansion of myeloid derived suppressor cells (MDSC). Intriguingly, PD-L1-, ILT-3-, and IDO-1-expressing monocytic MDSC were the dominant producers of IL-6 and IL-10, which correlated with the increased inflammation and accumulation of regulatory B and T cell subsets in severe COVID-19 patients. Overall, down-regulated IRF-8 and autophagy-related genes expression, and the expansion of MDSC subsets could play critical roles in dysregulating T cell response in COVID-19, which could have large implications in diagnostics and design of novel therapeutics for this disease.

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