Loss of Circulating CD8+ CD161high T Cells in Primary Progressive Multiple Sclerosis

Acquaviva, Massimo; Bassani, Claudia; Sarno, Nicole; Costa, Gloria Dalla; Romeo, Marzia; Sangalli, Francesca; Colombo, Bruno; Moiola, Lucia; Martinelli, Vittorio; Comı, Gıancarlo; Farina, Cinthia

doi:10.3389/fimmu.2019.01922

Cited by 11 publications

(10 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Acquaviva et al. ( 40 ) showed that the gene expression of both IL17 and C-type lectin CD161, controlled by the transcription factor RORγt, is not only a feature of Th17 cells but also of a particular CD3+CD8+ cell type. Hinks and Zhang ( 41 ) described CD8+CD161 high cells, known as mucosal-associated invariant T (MAIT) cells.…”

Section: Discussionmentioning

confidence: 99%

“…The frequency of CD3+CD8+CD161+ lymphocytes decreased in blood but increased in the inflamed site by infiltrating MS lesions. Seventy to eighty percent of CD3+CD8+ cells from active MS lesions are known to produce IL17 ( 40 ). Patients with MS have a significantly higher percentage of peripheral blood CD3+CD8+CD161 high cells, which secrete more IL17 than in healthy individuals.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

et al. 2021

View full text Add to dashboard Cite

BackgroundMultiple sclerosis (MS) is an incurable autoimmune disease mediated by a heterogeneous T cell population (CD3+CD161+CXCR3−CCR6+IFNγ−IL17+, CD3+CXCR3+CCR6+IFNγ+IL17+, and CD3+CXCR3+IFNγ+IL17− phenotypes) that infiltrates the central nervous system, eliciting local inflammation, demyelination and neurodegeneration. Cladribine is a lymphocyte-depleting deoxyadenosine analogue recently introduced for MS therapy as a Disease Modifying Drug (DMD). Our aim was to establish a method for the early identification and prediction of cladribine responsiveness among MS patients.MethodsAn experimental model was designed to study the cytotoxic and immunomodulatory effect of cladribine. T cell subsets of naïve relapsing-remitting MS (RRMS) patients were analyzed ex vivo and in vitro comparatively to healthy controls (HC). Surviving cells were stimulated with rh-interleukin-2 for up to 14days. Cell proliferation and immunophenotype changes were analyzed after maximal (phorbol myristate acetate/ionomycin/monensin) and physiological T-cell receptor (CD3/CD28) activation, using multiparametric flow cytometry and xMAP technology.ResultsEx vivo CD161+Th17 cells were increased in RRMS patients. Ex vivo to in vitro phenotype shifts included: decreased CD3+CCR6+ and CD3+CD161+ in all subjects and increased CD3+CXCR3+ in RRMS patients only; Th17.1 showed increased proliferation vs Th17 in all subjects; CD3+IL17+ and CD3+IFNγ+IL17+ continued to proliferate till day 14, CD3+IFNγ+ only till day 7. Regarding cladribine exposure: RRMS CD3+ cells were more resistant compared to HC; treated CD3+ cells proliferated continuously for up to 14 days, while untreated cells only up to 7 days; both HC/RRMS CD3+CXCR3+ populations increased from baseline till day 14; in RRMS patients vs HC, IL17 secretion from cladribine-treated cells increased significantly, in line with the observed proliferation of CD3+IL17+ and CD3+IFNγ+IL17+ cells; in both HC/RRMS, cladribine led to a significant increase in CD3+IFNγ+ cells at day 7 only, having no further effect at day14. IFNγ and IL17 secreted in culture media decreased significantly from ex vivo to in vitro.ConclusionsCD3+ subtypes showed different responsiveness due to selectivity of cladribine action, in most patients leading to in vitro survival/proliferation of lymphocyte subsets known as pathogenic in MS. This in vitro experimental model is a promising tool for the prediction of individual responsiveness of MS patients to cladribine and other DMDs.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

et al. 2021

View full text Add to dashboard Cite

show abstract

“…A higher frequency of circulating CD8+ CD161high TCR-Va7.2+ MAIT cells was found in relapsing remitting adult MS (220) and pediatric onset MS (221). Other studies reported a decrease in CD8 MAIT cell frequency in relapsing remitting (222,223) and primary progressive MS (224,225) or no differences between MS patients and healthy donors in MAIT frequency, phenotype and activation potential (226). CD8 T cells with MAIT cell-related features were also found in CNS lesions at a seemingly low frequency (220,223,226,227).…”

Section: Cd8 T Cell Subsets In Msmentioning

confidence: 98%

The CD8 T Cell-Epstein-Barr Virus-B Cell Trialogue: A Central Issue in Multiple Sclerosis Pathogenesis

Veroni

Aloisi

2021

Front. Immunol.

View full text Add to dashboard Cite

The cause and the pathogenic mechanisms leading to multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), are still under scrutiny. During the last decade, awareness has increased that multiple genetic and environmental factors act in concert to modulate MS risk. Likewise, the landscape of cells of the adaptive immune system that are believed to play a role in MS immunopathogenesis has expanded by including not only CD4 T helper cells but also cytotoxic CD8 T cells and B cells. Once the key cellular players are identified, the main challenge is to define precisely how they act and interact to induce neuroinflammation and the neurodegenerative cascade in MS. CD8 T cells have been implicated in MS pathogenesis since the 80’s when it was shown that CD8 T cells predominate in MS brain lesions. Interest in the role of CD8 T cells in MS was revived in 2000 and the years thereafter by studies showing that CNS-recruited CD8 T cells are clonally expanded and have a memory effector phenotype indicating in situ antigen-driven reactivation. The association of certain MHC class I alleles with MS genetic risk implicates CD8 T cells in disease pathogenesis. Moreover, experimental studies have highlighted the detrimental effects of CD8 T cell activation on neural cells. While the antigens responsible for T cell recruitment and activation in the CNS remain elusive, the high efficacy of B-cell depleting drugs in MS and a growing number of studies implicate B cells and Epstein-Barr virus (EBV), a B-lymphotropic herpesvirus that is strongly associated with MS, in the activation of pathogenic T cells. This article reviews the results of human studies that have contributed to elucidate the role of CD8 T cells in MS immunopathogenesis, and discusses them in light of current understanding of autoreactivity, B-cell and EBV involvement in MS, and mechanism of action of different MS treatments. Based on the available evidences, an immunopathological model of MS is proposed that entails a persistent EBV infection of CNS-infiltrating B cells as the target of a dysregulated cytotoxic CD8 T cell response causing CNS tissue damage.

show abstract

“…In MS brain infiltrates, 10% of all CD8 + T cells were IFN-g producing CD161 + cells that also secreted IL-17 and IL-22 and contributed to the pathogenesis of the disease (64). Activation induced expansion of CD161 cells and the implication of CD161 polymorphism in MS suggests potential therapeutic modulation of these cells in disease conditions mediated or ameliorated by CD8 + T-cells (40,65,66). In SLE, a disease in which CD8 + cells play a relatively minor role in pathogenesis, reduced CD161 expression on CD8 + T cells and NKT cells was noted in patients with advanced disease (67).…”

Section: Il-17 Producing Cd161 + T Cells Implicated In Auto-immune Diseasesmentioning

confidence: 99%

CD8+CD161+ T-Cells: Cytotoxic Memory Cells With High Therapeutic Potential

et al. 2021

View full text Add to dashboard Cite

NK1.1 and its human homolog CD161 are expressed on NK cells, subsets of CD4+ and CD8+ T cells, and NKT cells. While the expression of NK1.1 is thought to be inhibitory to NK cell function, it is reported to play both costimulatory and coinhibitory roles in T-cells. CD161 has been extensively studied and characterized on subsets of T-cells that are MR1-restricted, IL-17 producing CD4+ (TH17 MAIT cells) and CD8+ T cells (Tc17 cells). Non-MAIT, MR1-independent CD161-expressing T-cells also exist and are characterized as generally effector memory cells with a stem cell like phenotype. Gene expression analysis of this enigmatic subset indicates a significant enhancement in the expression of cytotoxic granzyme molecules and innate like stress receptors in CD8+NK1.1+/CD8+CD161+ cells in comparison to CD8+ cells that do not express NK1.1 or CD161. First identified and studied in the context of viral infection, the role of CD8+CD161+ T-cells, especially in the context of tumor immunology, is still poorly understood. In this review, the functional characteristics of the CD161-expressing CD8+ T cell subset with respect to gene expression profile, cytotoxicity, and tissue homing properties are discussed, and application of this subset to immune responses against infectious disease and cancer is considered.

show abstract

Loss of Circulating CD8+ CD161high T Cells in Primary Progressive Multiple Sclerosis

Cited by 11 publications

References 32 publications

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

The CD8 T Cell-Epstein-Barr Virus-B Cell Trialogue: A Central Issue in Multiple Sclerosis Pathogenesis

CD8+CD161+ T-Cells: Cytotoxic Memory Cells With High Therapeutic Potential

Contact Info

Product

Resources

About