Faculty Opinions recommendation of In human alloreactive CD4⁺ T-cells, dichloroacetate inhibits aerobic glycolysis, induces apoptosis and favors differentiation towards the regulatory T-cell subset instead of effector T-cell subsets.

Background:Aberrant T cell responses are key in driving autoimmunity and are commonly associated with rheumatoid arthritis (RA). Unravelling pathways of importance in therapeutic partial response and failure is of critical importance, as this will potentially provide new insights into key drivers of immune-mediated pathogenesis.Objectives:To delineate disease-relevant T cell subsets in RA and assess their potential to act as cellular markers amenable to precision medicine approaches, particularly in the context of therapeutic partial or non-response.Methods:FACS-based immunophenotyping and ex-vivo functional response profiles of CD4+CD161+CCR2+CCR5+T cells were performed in peripheral blood mononuclear cells (PBMC) obtained from patients with RA and healthy controls, using previously characterised methodologies. RA patients fulfilled the 2010 ACR/EULAR criteria for RA. All samples were obtained after written consent, with the appropriate ethical approvals in place.Results:RA patients harboured a higher frequency of CCR2+CCR5+cells within the CD4+CD161+T cell compartment compared with healthy controls. In RA patients this T cell subset had a higher proportion of cells that secrete pro-inflammatory cytokines such as IL-17A, GM-CSF, IFN-γ, and TNF. Importantly, the CD4+CD161+CCR2+CCR5+T cell subset was significantly increased in DMARD non-responders compared to both responders and healthy controls. Moreover, in DMARD non-responders, these cells had a propensity to express increased proportions of pro-inflammatory cytokines. Notably, there was also a significant increase in the ratio of effector: regulatory T cell (Teff: Treg) compared to both responders and healthy controls. In addition, the CD4+CD161+CCR2+CCR5+T cell subset was less responsive to suppression by Tregs. In further support of a role for this T cell population in disease pathogenesis, the frequency of CD4+CD161+CCR2+CCR5+T cells significantly correlated with disease activity, as measured by the DAS28 (R2= 0.65; p = 0.003; n=11).Conclusion:Combined, our findings suggest that the CD4+CD161+CCR2+CCR5+T cell subset represents a substantially abnormal T cell subset in RA, exhibiting exaggerated pro-inflammatory responses, numerical abundance relative to Tregs, and resistant to regulation by Tregs. The CD4+CD161+CCR2+CCR5+T cell subset appears to be a marker of therapeutic response status in RA, via its contribution to disease pathology and highlights this subset as a potential therapeutic target in RA.References:[1]McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis.N Engl J Med. 2011;365(23):2205-19.[2]Mexhitaj I, Nyirenda MH, Li R, O’Mahony J, Rezk A, Rozenberg A,et al. Abnormal effector and regulatory T cell subsets in paediatric-onset multiple sclerosis.Brain. 2019;142(3):617-32.[3]Cosmi L, Cimaz R, Maggi L, Santarlasci V, Capone M, Borriello F,et al. Evidence of the transient nature of the Th17 phenotype of CD4+CD161+T cells in the synovial fluid of patients with juvenile idiopathic arthritis.Arthritis Rheum. 2011;63(8):2504-15.Disclosure of Interests:Mukanthu Nyirenda: None declared, Iain McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB, Carl Goodyear: None declared

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Single cell sequencing reveals expanded cytotoxic CD4+ T cells and two states of peripheral helper T cells in synovial fluid of ACPA+ RA patients

10.1101/2021.05.28.21255902 ◽

2021 ◽

Author(s):

Alexandra Argyriou ◽

Marc H Wadsworth ◽

Adrian Lendvai ◽

Stephen M Christensen ◽

Aase Hensvold ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Synovial Fluid ◽

Single Cell ◽

Cd4 T Cells ◽

Cell Subset ◽

T Cell Subsets ◽

Cd4 T Cell ◽

T Cell Subset ◽

Single Cell Sequencing

Rheumatoid arthritis is an autoimmune disease affecting the synovial joints where different subsets of CD4+ T cells are suspected to play a pathogenic role. So far, our understanding of the contribution of cytotoxic CD4+ T cells is incomplete, particularly in the context of the recently described peripheral helper T-cell subset (TPH). Here, using single cell sequencing and multi-parameter flow cytometry, we show that cytotoxic CD4+ T cells are enriched in synovial fluid of anti-citrullinated peptides antibody (ACPA)-positive RA patients. We identify two distinct TPH states differentially characterized by the expression of CXCL13 and PRDM1, respectively. Our data reveal that the adhesion G-Protein Coupled Receptor 56 (GPR56), a marker of circulating cytotoxic cells, delineates the synovial TPH CD4+ T-cell subset. At the site of inflammation, GPR56+CD4+ T cells expressed the tissue-resident memory markers LAG-3, CXCR6 and CD69. Further, TCR clonality analysis revealed that most expanded clones in SF are contained within the cytotoxic and the CXCL13+ TPH CD4+ T-cell populations. Finally, the detection of common TCRs between the two TPH and cytotoxic CD4+ T-cell clusters suggest a shared differentiation. Our study provides comprehensive immunoprofiling of the heterogenous T-cell subsets at the site of inflammation in ACPA+ RA and suggests GPR56 as a therapeutic target to modulate TPH cells and cytotoxic CD4+ T cell function

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Reconstitution of T Cell Subsets Following Allogeneic Hematopoietic Cell Transplantation

Cancers ◽

10.3390/cancers12071974 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1974 ◽

Cited By ~ 1

Author(s):

Linde Dekker ◽

Coco de Koning ◽

Caroline Lindemans ◽

Stefan Nierkens

Keyword(s):

Overall Survival ◽

T Cells ◽

T Cell ◽

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Cell Subset ◽

Γδ T Cells ◽

Hematopoietic Cell ◽

T Cell Subsets ◽

T Cell Subset

Allogeneic (allo) hematopoietic cell transplantation (HCT) is the only curative treatment option for patients suffering from chemotherapy-refractory or relapsed hematological malignancies. The occurrence of morbidity and mortality after allo-HCT is still high. This is partly correlated with the immunological recovery of the T cell subsets, of which the dynamics and relations to complications are still poorly understood. Detailed information on T cell subset recovery is crucial to provide tools for better prediction and modulation of adverse events. Here, we review the current knowledge regarding CD4+ and CD8+ T cells, γδ T cells, iNKT cells, Treg cells, MAIT cells and naive and memory T cell reconstitution, as well as their relations to outcome, considering different cell sources and immunosuppressive therapies. We conclude that the T cell subsets reconstitute in different ways and are associated with distinct adverse and beneficial events; however, adequate reconstitution of all the subsets is associated with better overall survival. Although the exact mechanisms involved in the reconstitution of each T cell subset and their associations with allo-HCT outcome need to be further elucidated, the data and suggestions presented here point towards the development of individualized approaches to improve their reconstitution. This includes the modulation of immunotherapeutic interventions based on more detailed immune monitoring, aiming to improve overall survival changes.

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Paraneoplastic myasthenia gravis correlates with generation of mature naive CD4+ T cells in thymomas

Blood ◽

10.1182/blood.v100.1.159 ◽

2002 ◽

Vol 100 (1) ◽

pp. 159-166 ◽

Cited By ~ 76

Author(s):

Philipp Ströbel ◽

Markus Helmreich ◽

Georgios Menioudakis ◽

Sharon R. Lewin ◽

Thomas Rüdiger ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Myasthenia Gravis ◽

Cell Sorting ◽

Cd4 T Cells ◽

Matched Control ◽

Cell Subset ◽

Autoreactive T Cells ◽

T Cell Subset ◽

Age And Sex

Abstract Myasthenia gravis (MG) is the leading paraneoplastic manifestation of thymomas and is probably related to the capacity of thymomas to mature and export potentially autoreactive T cells. Why some thymomas are MG associated (MG+) and others are not (MG−) has been unclear. We addressed this question by comparing the percentages of intratumorous naive mature CD45RA+ thymocytes in 9 MG(+) and in 13 MG(−) thymomas by fluorescence-activated cell sorting analysis. Our results show that intratumorous naive CD4 T cells were present in all MG(+) thymomas and in one MG(−) thymoma with the development of MG only 2 months after surgery. By contrast, the percentage of naive CD4+ T cells was significantly reduced in all 13 MG(−) thymomas (P < .0001). Alterations in intratumorous thymopoiesis were reflected by corresponding alterations of naive T-cell subset composition in the blood, in that only MG(−) patients had significantly decreased levels (P = .02) of naive CD4+ T cells compared with age- and sex-matched control persons. We conclude that paraneoplastic MG is highly associated with the efficiency of thymomas to produce and export naive CD4+T cells. The acquisition of the CD45RA+ phenotype on CD4+ T cells during terminal intratumorous thymopoiesis is associated with the presence of MG in most thymoma patients.

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In vivo T-cell subset depletion suggests that CD4+ T-cells and a humoral immune response are important for the elimination of orf virus from the skin of sheep

Veterinary Immunology and Immunopathology ◽

10.1016/s0165-2427(00)00178-1 ◽

2000 ◽

Vol 74 (3-4) ◽

pp. 249-262 ◽

Cited By ~ 21

Author(s):

J.B Lloyd ◽

H.S Gill ◽

D.M Haig ◽

A.J Husband

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Humoral Immune Response ◽

Cd4 T Cells ◽

Cell Subset ◽

Orf Virus ◽

T Cell Subset ◽

Humoral Immune

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CD8+CD44hi but not CD4+CD44hi memory T cells mediate potent graft antilymphoma activity without GVHD

Blood ◽

10.1182/blood-2010-10-312751 ◽

2011 ◽

Vol 117 (11) ◽

pp. 3230-3239 ◽

Cited By ~ 29

Author(s):

Suparna Dutt ◽

Jeanette Baker ◽

Holbrook E. Kohrt ◽

Neeraja Kambham ◽

Mrinmoy Sanyal ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Memory T Cells ◽

Cell Subset ◽

B Cell Lymphoma ◽

Effector Memory ◽

T Cell Subset ◽

Progressive Growth

Abstract Allogeneic hematopoietic cell transplantation can be curative in patients with leukemia and lymphoma. However, progressive growth of malignant cells, relapse after transplantation, and graft-versus-host disease (GVHD) remain important problems. The goal of the current murine study was to select a freshly isolated donor T-cell subset for infusion that separates antilymphoma activity from GVHD, and to determine whether the selected subset could effectively prevent or treat progressive growth of a naturally occurring B-cell lymphoma (BCL1) without GVHD after recipients were given T cell–depleted bone marrow transplantations from major histocompatibility complex–mismatched donors. Lethal GVHD was observed when total T cells, naive CD4+ T cells, or naive CD8+ T cells were used. Memory CD4+CD44hi and CD8+CD44hi T cells containing both central and effector memory cells did not induce lethal GVHD, but only memory CD8+ T cells had potent antilymphoma activity and promoted complete chimerism. Infusion of CD8+ memory T cells after transplantation was able to eradicate the BCL1 lymphoma even after progressive growth without inducing severe GVHD. In conclusion, the memory CD8+ T-cell subset separated graft antilymphoma activity from GVHD more effectively than naive T cells, memory CD4+ T cells, or memory total T cells.

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CD4+ T-Cell Plasticity in Non-Infectious Retinal Inflammatory Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22179584 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9584

Author(s):

Yi-Hsing Chen ◽

Sue Lightman ◽

Virginia L. Calder

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Th17 Cells ◽

Cell Subset ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Dual Function ◽

Interleukin 17 ◽

Th1 Cells

Non-infectious uveitis (NIU) is a potentially sight-threatening disease. Effector CD4+ T cells, especially interferon-γ-(IFNγ) producing Th1 cells and interleukin-17-(IL-17) producing Th17 cells, are the major immunopathogenic cells, as demonstrated by adoptive transfer of disease in a model of experimental autoimmune uveitis (EAU). CD4+FoxP3+CD25+ regulatory T cells (Tregs) were known to suppress function of effector CD4+ T cells and contribute to resolution of disease. It has been recently reported that some CD4+ T-cell subsets demonstrate shared phenotypes with another CD4+ T-cell subset, offering the potential for dual function. For example, Th17/Th1 (co-expressing IFNγ and IL-17) cells and Th17/Treg (co-expressing IL-17 and FoxP3) cells have been identified in NIU and EAU. In this review, we have investigated the evidence as to whether these ‘plastic CD4+ T cells’ are functionally active in uveitis. We conclude that Th17/Th1 cells are generated locally, are resistant to the immunosuppressive effects of steroids, and contribute to early development of EAU. Th17/Treg cells produce IL-17, not IL-10, and act similar to Th17 cells. These cells were considered pathogenic in uveitis. Future studies are needed to better clarify their function, and in the future, these cell subsets may in need to be taken into consideration for designing treatment strategies for disease.

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DOP29 Elevation of a novel blood-based gene signature in a severe Crohn’s disease (CD) subtype preceding surgery defines and predicts a post-surgical decrease in pro-inflammatory pathway activation

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.068 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S068-S069

Author(s):

R Gonsky ◽

P Fleshner ◽

G Botwin ◽

E Biener-Ramanujan ◽

D McGovern ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

T Cell ◽

Cell Subset ◽

Gene Signature ◽

T Cell Subsets ◽

T Cell Subset ◽

Post Surgery ◽

Cell Gene Expression ◽

Cell Gene

Abstract Background CD is defined by transmural inflammation leading to inflammatory, stricturing and/or penetrating phenotypes. Identifying underlying molecular pathways and distinct disease subsets is critical for improved prognostics, therapeutics and biomarker discovery. Methods CD3+ T cells were purified from paired blood and mucosal tissue from 101 CD and 17 non-IBD subjects requiring surgery. Longitudinal samples (n = 30) were collected 4–13 mo. post-surgery. Expression profiles were generated by RNAseq, T-cell subset deconvolution by xCell and transcriptome-wide associations (TWAS) using TWAS-hub. Results Unsupervised clustering of peripheral T-cell gene expression at surgery revealed 2 CD profiles: Expression from cluster1, labelled CD-PBT (63%), clustered tightly with the non-IBD group. In cluster2, expression shifted from a peripheral toward a mucosal profile, labelled CD-PBmu(cosal) (37%). CD-PBmu was defined by differentially expressed genes (DEG) (1944 DEG, p < 0.001) regulating cell migration and adhesion pathways and a distinct T-cell subset composition associated with stricturing disease (p = 0.03), increased resected bowel length (p = 0.036) and post-op recurrence (p = 0.01). There were no significant differences in disease location/behaviour. Independent validation (5 public datasets) confirmed the CD-PBmu signature in data from whole blood (CD patients failing anti-TNF therapy, n = 204) and the mucosal-like expression profile in data from ileal tissue (paediatric CD patients, studies n = 751). A defining feature of CD-PBmu, validated in a separate CD cohort (n = 19), was decreased pro-inflammatory cytokine/chemokine and adhesion molecule expression following surgery (900 DEG, p < 0.001). No post-surgery change in expression was detected in CD-PBT. A 44-gene classifier was identified to enable clinical application. The classifier accurately detected the CD-PBmu patient subtype, correlated with the altered composition of peripheral T-cell subsets and overlapped with IBD associated TWAS signals (>60%). Recently, another group posed a blood-based 17 gene panel as predictive for aggressive IBD. These genes were not predictive for either the CD-PBmu or CD-PBT subtype (<50% DEG). Conclusion Severe CD can be stratified into 2 subtypes based on peripheral T-cell gene expression. Circulating T cells from CD-PBmu exhibit a mucosal-like gene signature, altered T-cell subset composition, clinical features of severity and decreased pro-inflammatory gene expression post-surgery. These findings hold potential to identify targets for CD subtype-specific therapeutic development. The 44-gene classifier overlapped with multiple paediatric CD datasets, suggesting the potential application of these findings for treatment stratification early in the disease process.

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Imbalance between CD8+CD28+ and CD8+CD28– T-cell subsets and its clinical significance in patients with systemic lupus erythematosus

Lupus ◽

10.1177/0961203319867130 ◽

2019 ◽

Vol 28 (10) ◽

pp. 1214-1223

Author(s):

S Minning ◽

Y Xiaofan ◽

X Anqi ◽

G Bingjie ◽

S Dinglei ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

T Cell ◽

Lupus Erythematosus ◽

Fas Ligand ◽

Activity Index ◽

Cell Subset ◽

T Cell Subsets ◽

Systemic Lupus ◽

T Cell Subset

Objective The aim of this study was to evaluate the changes in CD8+CD28–/CD8+CD28+ T-cell subset balance and in the CD8+CD28– Treg cell number and function in patients with systemic lupus erythematosus (SLE). Methods Cell isolation and flow cytometry analysis were employed to investigate the T-cell subsets. Results It was found that in high-activity SLE patients, the CD8+CD28+ T-cell subset was reduced, which was inversely correlated with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and that the CD8+CD28–/CD8+CD28+ ratio was elevated, which was positively correlated with SLEDAI and with renal damage and inversely correlated with serum complement level, whereas the CD8+CD28– T-cell subset was increased only in inactive patients. It was also found that apoptosis of CD8+ T cells increased, and Fas, Fas ligand (FasL) and interleukin (IL)-6 expression were high, whereas cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) expression was low by the CD8+CD28+ T cell subset in active SLE patients; apoptosis was positively correlated with SLEDAI and with the expression of Fas and FasL by the CD8+CD28+ T-cell subset in active SLE patients. IL-6 and CTLA-4 expression were found to be low by the CD8+CD28– T cell subset in active SLE patients. Conclusion These data suggest that high expression of Fas, FasL and IL-6 and low expression of CTLA-4 by the CD8+CD28+ T-cell subset promotes the activation-induced cell death of the CD8+CD28+ T-cell subset, resulting in an imbalance of CD8+CD28–/CD8+CD28+ T cells in active SLE patients, which represents an important feature in the immunological pathogenesis of SLE. The CD8+CD28– T-cell subset may play some role in inactive SLE.

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