Prognostic significance of interleukin-17A-producing colorectal tumour antigen-specific T cells

Abstract Background The T cell cytokine profile is a key prognostic indicator of post-surgical outcome for colorectal cancer (CRC). Whilst TH1 (IFN-γ+) cell-mediated responses generated in CRC are well documented and are associated with improved survival, antigen-specific TH17 (IL-17A+) responses have not been similarly measured. Methods We sought to determine the cytokine profile of circulating tumour antigen-(5T4/CEA) specific T cells of 34 CRC patients to address whether antigen-specific IL-17A responses were detectable and whether these were distinct to IFN-γ responses. Results As with IFN-γ-producing T cells, anti-5T4/CEA TH17 responses were detectable predominantly in early stage (TNM I/II) CRC patients. Moreover, whilst IL-17A was always produced in association with IFN-γ, this release was mainly from two distinct T cell populations rather than by ‘dual producing’ T cells. Patients mounting both tumour-specific TH1+/TH17+ responses exhibited prolonged relapse-free survival. Conclusions Tumour antigen-specific TH17 responses play a beneficial role in preventing post-operative colorectal tumour recurrence.

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Accumulation of Human Heat Shock Protein 60-Reactive T Cells in the Gingival Tissues of Periodontitis Patients

Infection and Immunity ◽

10.1128/iai.70.5.2492-2501.2002 ◽

2002 ◽

Vol 70 (5) ◽

pp. 2492-2501 ◽

Cited By ~ 74

Author(s):

Kazuhisa Yamazaki ◽

Yutaka Ohsawa ◽

Koichi Tabeta ◽

Harue Ito ◽

Kaoru Ueki ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Heat Shock ◽

Heat Shock Protein ◽

Peripheral Blood ◽

Cytokine Profile ◽

T Cell Clones ◽

Cell Clones ◽

Ifn Γ ◽

Human Hsp60

ABSTRACT Heat shock protein 60s (hsp60) are remarkably immunogenic, and both T-cell and antibody responses to hsp60 have been reported in various inflammatory conditions. To clarify the role of hsp60 in T-cell responses in periodontitis, we examined the proliferative response of peripheral blood mononuclear cells (PBMC), as well as the cytokine profile and T-cell clonality, for periodontitis patients and controls following stimulation with recombinant human hsp60 and Porphyromonas gingivalis GroEL. To confirm the infiltration of hsp60-reactive T-cell clones into periodontitis lesions, nucleotide sequences within complementarity-determining region 3 of the T-cell receptor (TCR) β-chain were compared between hsp60-reactive peripheral blood T cells and periodontitis lesion-infiltrating T cells. Periodontitis patients demonstrated significantly higher proliferative responses of PBMC to human hsp60, but not to P. gingivalis GroEL, than control subjects. The response was inhibited by anti-major histocompatibility complex class II antibodies. Analysis of the nucleotide sequences of the TCR demonstrated that human hsp60-reactive T-cell clones and periodontitis lesion-infiltrating T cells have the same receptors, suggesting that hsp60-reactive T cells accumulate in periodontitis lesions. Analysis of the cytokine profile demonstrated that hsp60-reactive PBMC produced significant levels of gamma interferon (IFN-γ) in periodontitis patients, whereas P. gingivalis GroEL did not induce any skewing toward a type1 or type2 cytokine profile. In control subjects no significant expression of IFN-γ or interleukin 4 was induced. These results suggest that periodontitis patients have human hsp60-reactive T cells with a type 1 cytokine profile in their peripheral blood T-cell pools.

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Investigating the Induction of Vaccine-Induced Th17 and Regulatory T Cells in Healthy, Mycobacterium bovis BCG-Immunized Adults Vaccinated with a New Tuberculosis Vaccine, MVA85A

Clinical and Vaccine Immunology ◽

10.1128/cvi.00047-10 ◽

2010 ◽

Vol 17 (7) ◽

pp. 1066-1073 ◽

Cited By ~ 43

Author(s):

Simone C. de Cassan ◽

Ansar A. Pathan ◽

Clare R. Sander ◽

Angela Minassian ◽

Rosalind Rowland ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Viral Vector ◽

T Cell Subsets ◽

Vector Vaccine ◽

Interleukin 17A ◽

Ifn Γ ◽

Immune Pathology ◽

Mycobacterial Antigens

ABSTRACT Tuberculosis (TB) remains a threat to global health. While advances in diagnostics and treatment are crucial to the containment of the epidemic, it is likely that elimination of the disease can only be achieved through vaccination. Vaccine-induced protection from Mycobacterium tuberculosis is dependent, at least in part, on a robust Th1 response, yet little is known of the ability of TB vaccines to induce other T-cell subsets which may influence vaccine efficacy. Interleukin-17A (IL-17A) is a proinflammatory cytokine produced by Th17 cells which has been associated with both immune pathology and protection against infectious disease. Following vaccination with MVA85A, a viral vector vaccine aimed at enhancing immune responses to M. tuberculosis, antigen-specific IL-17A-producing T cells were induced in the peripheral blood of healthy volunteers. These T cells are detected later than gamma interferon (IFN-γ)-secreting T cells and are of a low magnitude. Preexisting immune responses to mycobacterial antigens were associated with higher CD4+ CD25hi CD39+ T-cell levels in the periphery and a reduced capacity to produce IL-17A following immunization. These data highlight the intricate balance of effector and regulatory immune responses induced by vaccination and that preexisting immunity to mycobacterial antigens may affect the composition of vaccine-induced T-cell subsets.

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Potent but transient immunosuppression of T-cells is a general feature of CD71+ erythroid cells

Communications Biology ◽

10.1038/s42003-021-02914-4 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Tomasz M. Grzywa ◽

Anna Sosnowska ◽

Zuzanna Rydzynska ◽

Michal Lazniewski ◽

Dariusz Plewczynski ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Mononuclear Cells ◽

Early Stage ◽

Dependent Manner ◽

Erythroid Cells ◽

Healthy Human ◽

Ifn Γ

AbstractCD71+ erythroid cells (CECs) have been recently recognized in both neonates and cancer patients as potent immunoregulatory cells. Here, we show that in mice early-stage CECs expand in anemia, have high levels of arginase 2 (ARG2) and reactive oxygen species (ROS). In the spleens of anemic mice, CECs expansion-induced L-arginine depletion suppresses T-cell responses. In humans with anemia, CECs expand and express ARG1 and ARG2 that suppress T-cells IFN-γ production. Moreover, bone marrow CECs from healthy human donors suppress T-cells proliferation. CECs differentiated from peripheral blood mononuclear cells potently suppress T-cell activation, proliferation, and IFN-γ production in an ARG- and ROS-dependent manner. These effects are the most prominent for early-stage CECs (CD71highCD235adim cells). The suppressive properties disappear during erythroid differentiation as more differentiated CECs and mature erythrocytes lack significant immunoregulatory properties. Our studies provide a novel insight into the role of CECs in the immune response regulation.

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Impaired T cell functions along with elevated activated Tregs at the early stage of asymptomatic SARS-CoV-2 infection

10.1101/2020.05.25.20108852 ◽

2020 ◽

Author(s):

Jingyi Yang ◽

Ejuan Zhang ◽

Maohua Zhong ◽

Qingyu Yang ◽

Ke Hong ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Early Stage ◽

Function Analysis ◽

T Cell Responses ◽

Cell Functions ◽

Cell Responses ◽

Ifn Γ

SummaryBackgroundLimited data are available on the T cell responses for the asymptomatic SARS-CoV-2 infection case.MethodsAn imported SARS-CoV-2 infection case in Wuhan was admitted in hospital for quarantine and observation. The T cell responses were followed up by flow cytometry analysis of the peripheral blood nonnuclear cells (PBMCs) at days 7, 13, 22, and 28 after admission.FindingsWe found the imported SARS-CoV-2 infection in Wuhan is an asymptomatic case. His T cell differentiation, proliferation and activation matched the classical kinetics of T cell responses induced by viral infection, but the activation maintained at a relatively low level. Function analysis indicated frequencies of IFN-γ producing CD4+ and CD8+ T cells were notably lower than that of the healthy controls (HC) at day 7, and then rebound gradually. But IFN-γ+CD8+ T cells were detained at a significant lower level even at day 28, when the SARS-CoV-2 virus had already become undetectable for 3 weeks. Moreover, percentage of IL-17 producing CD4+ T cells was also detained constantly at a much lower level compared to HC. At day 7, although percentage of Tregs was in normal range, the frequency of activated Treg (aTreg) was remarkably as high as 4·4-fold of that in HC.InterpretationThe T cell activation in the asymptomatic SARS-CoV-2 infection experienced a significant suppression and presented impairment of Th1/Th17 and CD8+ T cell functions. Early elevation of the aTregs might play role in the activation and function of T cells in the asymptomatic SARS-CoV-2 infection.

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Distinct tumour antigen-specific T-cell immune response profiles at different hepatocellular carcinoma stages

BMC Cancer ◽

10.1186/s12885-021-08720-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chaoran Zang ◽

Yan Zhao ◽

Ling Qin ◽

Guihai Liu ◽

Jianping Sun ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Response ◽

T Cell ◽

Early Stage ◽

T Cell Responses ◽

Tumour Antigen ◽

Cell Immune Response ◽

Cell Responses ◽

Ifn Γ

Abstract Background Cancer-testis antigens (CTAs) and tumour-associated antigens (TAAs) are frequently expressed in hepatocellular carcinoma (HCC); however, the role of tumour-antigen-specific T cell immunity in HCC progression is poorly defined. We characterized CTA- and TAA-specific T cell responses in different HCC stages and investigated their alterations during HCC progression. Methods Fifty-eight HCC patients, 15 liver cirrhosis patients, 15 chronic hepatitis B patients and 10 heathy controls were enrolled in total. IFN-γ ELSPOT using CTAs, including MAGE-A1, MAGE-A3, NY-ESO-1, and SSX2, and two TAAs, SALL4 and AFP, was performed to characterize the T-cell immune response in the enrolled individuals. The functional phenotype of T cells and the responsive T cell populations were analyzed using short-term T-cell culture. Results T cell responses against CTAs and TAAs were specific to HCC. In early-stage HCC patients, the SALL4-specific response was the strongest, followed by MAGE-A3, NY-ESO-1, MAGE-A1 and SSX2. One-year recurrence-free survival after transcatheter arterial chemoembolization plus radiofrequency ablation treatment suggested the protective role of CTA-specific responses. The four CTA- and SALL4-specific T cell responses decreased with the progression of HCC, while the AFP-specific T cell response increased. A higher proportion of CD4+ T cells specific to CTA/SALL4 was observed than AFP-specific T cell responses. Conclusions The IFN-γ ELISPOT assay characterized distinct profiles of tumour-antigen-specific T cell responses in HCC patients. CTA- and SALL4-specific T cell responses may be important for controlling HCC in the early stage, whereas AFP-specific T cell responses might be a signature of malignant tumour status in the advanced stage. The application of immunotherapy at an early stage of HCC development should be considered.

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Cytokine profile of sipuleucel-T (sip-T) in differentiating reactivation of latent immunity from de novo immune responses.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.7_suppl.163 ◽

2017 ◽

Vol 35 (7_suppl) ◽

pp. 163-163

Author(s):

Charles G. Drake ◽

Daniel Peter Petrylak ◽

Emmanuel S. Antonarakis ◽

Adam S. Kibel ◽

Nancy N. Chang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Cd8 T Cells ◽

Mononuclear Cells ◽

De Novo ◽

T Cell Response ◽

Cytokine Profile ◽

Castration Resistant Prostate Cancer ◽

Ifn Γ

163 Background: Sip-T is an FDA-approved immunotherapy for treating patients (pts) with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). It is manufactured from autologous peripheral blood mononuclear cells (PBMCs) cultured with PA2024, a fusion of prostatic acid phosphatase (PAP) and granulocyte macrophage colony-stimulating factor. Survival of sip-T–treated mCRPC pts correlates with immune responses to PA2024 and/or PAP. PA2024- or PAP-specific CD4+ and CD8+ T cell proliferation and cytokine production and release were assessed to better understand sip-T–induced T cell responses. Methods: Pts with biochemical recurrence or mCRPC were from sip-T trials (NCT01431391, NCT01981122). PBMCs collected at baseline through 6 mo post–sip-T were cultured in vitro and stimulated with PA2024 or PAP. CD4+ and CD8+ T cells were assessed (n=19) for proliferation and intracellular IL-2 and IFN-γ. The cytokine profile was confirmed in supernatant with a meso scale discovery assay. P<0.10 was statistically significant. Results: Compared with baseline, PA2024-specific proliferating CD4+ and CD8+ T cells had increased intracellular IL-2 and IFN-γ levels at wk 6 and mo 6, with a similar trend for PAP-specific proliferating T cells (Table 1). Compared with unstimulated controls, a significant >2-fold increase in PA2024-stimulated IL-2 and IFN-γ in supernatant was observed at wk 6 and mo 6 over baseline (p<0.001). PAP-stimulated IL-2 and IFN-γ supernatant levels increased over baseline and were significantly elevated for IFN-γ at wk 6 (p<0.10). Conclusions: Sip-T therapy generated a de novo PA2024-specific T cell response, as indicated by the cytokine release profile. The PAP-stimulated cytokine profile suggests that pre-existing immunity with terminally differentiated T cells are expanded. Thus, sip-T reactivated an anti-PAP response in memory T cells, thereby overcoming immunosuppressive mechanisms in PC. Clinical trial information: NCT01431391; NCT01981122. [Table: see text]

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DsbA-L deficiency in T cells promotes diet-induced thermogenesis through suppressing IFN-γ production

Nature Communications ◽

10.1038/s41467-020-20665-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Haiyan Zhou ◽

Xinyi Peng ◽

Jie Hu ◽

Liwen Wang ◽

Hairong Luo ◽

...

Keyword(s):

T Cells ◽

Adipose Tissue ◽

T Cell ◽

Energy Homeostasis ◽

Metabolic Diseases ◽

Therapeutic Potential ◽

Whole Body ◽

Brown Adipose ◽

Ifn Γ ◽

Diet Induced Thermogenesis

AbstractAdipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding greatly suppresses the expression of disulfide-bond A oxidoreductase-like protein (DsbA-L), a mitochondria-localized chaperone protein, in adipose-resident T cells, which correlates with reduced T cell mitochondrial function. T cell-specific knockout of DsbA-L enhances diet-induced thermogenesis in brown adipose tissue (BAT) and protects mice from HFD-induced obesity, hepatosteatosis, and insulin resistance. Mechanistically, DsbA-L deficiency in T cells reduces IFN-γ production and activates protein kinase A by reducing phosphodiesterase-4D expression, leading to increased BAT thermogenesis. Taken together, our study uncovers a mechanism by which T cells communicate with brown adipocytes to regulate BAT thermogenesis and whole-body energy homeostasis. Our findings highlight a therapeutic potential of targeting T cells for the treatment of over nutrition-induced obesity and its associated metabolic diseases.

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CCL19 enhances CD8+ T-cell responses and accelerates HBV clearance

Journal of Gastroenterology ◽

10.1007/s00535-021-01799-8 ◽

2021 ◽

Author(s):

Yan Yan ◽

Wei Zhao ◽

Wei Liu ◽

Yan Li ◽

Xu Wang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Crucial Role ◽

Cell Activation ◽

Hbv Infection ◽

Host Immune System ◽

Tnf Α ◽

Ifn Γ ◽

High Level

Abstract Background Chemokine (C–C motif) ligand 19 (CCL19) is a leukocyte chemoattractant that plays a crucial role in cell trafficking and leukocyte activation. Dysfunctional CD8+ T cells play a crucial role in persistent HBV infection. However, whether HBV can be cleared by CCL19-activated immunity remains unclear. Methods We assessed the effects of CCL19 on the activation of PBMCs in patients with HBV infection. We also examined how CCL19 influences HBV clearance and modulates HBV-responsive T cells in a mouse model of chronic hepatitis B (CHB). In addition, C–C chemokine-receptor type 7 (CCR7) knockdown mice were used to elucidate the underlying mechanism of CCL19/CCR7 axis-induced immune activation. Results From in vitro experiments, we found that CCL19 enhanced the frequencies of Ag-responsive IFN-γ+ CD8+ T cells from patients by approximately twofold, while CCR7 knockdown (LV-shCCR7) and LY294002 partially suppressed IFN-γ secretion. In mice, CCL19 overexpression led to rapid clearance of intrahepatic HBV likely through increased intrahepatic CD8+ T-cell proportion, decreased frequency of PD-1+ CD8+ T cells in blood and compromised suppression of hepatic APCs, with lymphocytes producing a significantly high level of Ag-responsive TNF-α and IFN-γ from CD8+ T cells. In both CCL19 over expressing and CCR7 knockdown (AAV-shCCR7) CHB mice, the frequency of CD8+ T-cell activation-induced cell death (AICD) increased, and a high level of Ag-responsive TNF-α and low levels of CD8+ regulatory T (Treg) cells were observed. Conclusions Findings in this study provide insights into how CCL19/CCR7 axis modulates the host immune system, which may promote the development of immunotherapeutic strategies for HBV treatment by overcoming T-cell tolerance.

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AB0133 INCREASED SOLUBLE SEMAPHORIN 4D/CD100 IN THE PLASMA OF SJÖGREN’S SYNDROME AND ITS EFFECTS ON HUMAN SALIVARY GLAND CELL AND CD4+ T CELL

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5162 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1367.1-1367

Author(s):

S. E. Kang ◽

S. U. Kim ◽

R. H. Kim ◽

H. J. Yoo ◽

Y. J. Lee ◽

...

Keyword(s):

T Cells ◽

Salivary Gland ◽

T Cell ◽

Tight Junction ◽

Sjogren's Syndrome ◽

Healthy Controls ◽

Human Salivary Gland ◽

Semaphorin 4D ◽

Aqp5 Expression ◽

Ifn Γ

Background:Semaphorin 4D (SEMA4D) / CD100, known as a subfamily of axonal guidance proteins, has also been reported to act as an immunoregulator in several infectious and inflammatory diseases [1]. Sjögren’s syndrome (SS) is a systemic autoimmune disease that primarily affects the exocrine glands by infiltrated lymphocytes resulting in dryness of mouth and eyes. IL-17 was reported to impair the integrity of tight junction barrier and attenuate the expression of aquaporin 5 (AQP5), causing salivary gland dysfunction in SS [2].Objectives:This study was aimed to evaluate the role of SEMA4D in patients with SS and investigate the effect of SEMA4D on human salivary gland epithelial cell (SGEC) and T cell.Methods:Soluble SEMA4D levels in plasma were measured by enzyme-linked immunosorbent assay (ELISA) from patients with SS, non-SS sicca and healthy controls. Immortalized human SGECs, originated from acini (NS-SV-AC) and duct (NS-SV-DC), were used to evaluate the effects of SEMA4D. CD4+T cells from human peripheral blood were isolated to determine the secretion of cytokines in response to SEMA4D. IFN-γ and IL-17 were used to determine the effects on AQP5 expression of SGEC.Results:The levels of soluble SEMA4D in plasma were increased in patients with SS (median [interquartile range]: 1221.3 [393.5] pg/mL) compared to non-SS sicca (940.2 [355.1] pg/mL,p= 0.006) or healthy controls (909.5 [108.0] pg/mL,p <0.0001). The levels of soluble SEMA4D in plasma were correlated with the levels of several autoantibodies including anti-SSA (Spearman’s rho = 0.358,p= 0.006), anti-SSB (rho = 0.350,p= 0.007), and anti-muscarinic receptor 3 (M3R) Ab (rho = 0.495,p< 0.001), and also correlated with total IgG (rho = 0.431,p= 0.002). SEMA4D-stimulated SGECs showed decreased expression of tight junctions such as occludin and Zo-1. CD4+T cells secreted IFN-γ (p= 0.025), IL-17 (p= 0.028), and IL-21 (p= 0.007) with SEMA4D stimulation. IFN-γ and IL-17 decreased AQP5 expression in SGECs.Conclusion:SEMA4D contributed to decreased expression of tight junction in SGECs. SEMA4D induced production of IFN-γ and IL-17 in CD4+T cells and these cytokine decreased AQP5 expression in SGECs.References:[1]Worzfeld T, Offermanns S. Nat Rev Drug Discov. 2014;13(8):603-21.[2]Bhattarai KR, Junjappa R, Handigund M, Kim HR, Chae HJ. Autoimmun Rev. 2018;17(4):376-90.Disclosure of Interests:None declared

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Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002269 ◽

2021 ◽

Vol 9 (6) ◽

pp. e002269

Author(s):

Shota Aoyama ◽

Ryosuke Nakagawa ◽

Satoshi Nemoto ◽

Patricio Perez-Villarroel ◽

James J Mulé ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Tumor Growth ◽

Ex Vivo ◽

T Cell Response ◽

Effector Function ◽

Checkpoint Blockade ◽

Necrosis Factor Alpha ◽

Ifn Γ

BackgroundThe temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth.MethodsC57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays.ResultsThe distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+ T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+ T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+ T cell populations, increased CD4+ and CD8+ TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth.ConclusionsDespite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+ T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+ tumors.

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