Helios, and not FoxP3, is the marker of activated Tregs expressing GARP/LAP

Elkord, Eyad; Samid, May Abd Al; Chaudhary, Belal

doi:10.18632/oncotarget.4771

Cited by 81 publications

(84 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… suggested CD15s + FoxP3 high as highly suppressive T regs , because depletion of CD15s + CD4 + T cells from human blood enhanced in‐vitro anti‐tumour and anti‐viral antigen responses. Moreover, Helios has been reported previously as a vital marker for highly suppressive T regs in the activated state, which express LAP and GARP (glycoprotein A repetitions predominant) and secrete interleukin (IL)‐10 . We found LAP expression mainly in Helios + T reg in both HD and PBC.…”

Section: Discussionmentioning

confidence: 55%

In-vitro effect of pembrolizumab on different T regulatory cell subsets

Toor

Khaja

Alkurd

et al. 2017

Clinical and Experimental Immunology

View full text Add to dashboard Cite

Programmed death-1 (PD-1) and interactions with PD-ligand 1 (PD-L1) play critical roles in the tumour evasion of immune responses through different mechanisms, including inhibition of effector T cell proliferation, reducing cytotoxic activity, induction of apoptosis in tumour-infiltrating T cells and regulatory T cell (T ) expansion. Effective blockade of immune checkpoints can therefore potentially eliminate these detrimental effects. The aim of this study was to investigate the effect of anti-PD-1 antibody, pembrolizumab, on various T subpopulations. Peripheral blood mononuclear cells (PBMC) from healthy donors (HD) and primary breast cancer patients (PBC) were treated in vitro with pembrolizumab, which effectively reduced PD-1 expression in both cohorts. We found that PD-1 was expressed mainly on CD4 CD25 T cells and pembrolizumab had a greater effect on PD-1 expression in CD4 CD25 T cells, compared to CD4 CD25 cells. In addition, pembrolizumab did not affect the expression levels of T -related markers, including cytotoxic T lymphocyte antigen-4 (CTLA-4), CD15s, latency-associated peptide (LAP) and Ki-67. Moreover, we report that CD15s is expressed mainly on forkhead box P3 (FoxP3) Helios T in HD, but it is expressed on FoxP3 Helios T subset in addition to FoxP3 Helios T in PBC. Pembrolizumab did not affect the levels of FoxP3 Helios T subsets in both cohorts. Taken together, our study suggests that pembrolizumab does not affect T or change their phenotype or function but rather blocks signalling via the PD-1/PD-L1 axis in activated T cells.

show abstract

Section: Discussionmentioning

confidence: 55%

In-vitro effect of pembrolizumab on different T regulatory cell subsets

Toor

Khaja

Alkurd

et al. 2017

Clinical and Experimental Immunology

View full text Add to dashboard Cite

show abstract

“…The phenotype of FrII was consistent with that of activated and suppressive Treg, being comprised predominantly of CD25 + CD127 lo (Supplementary Figure S1A) and Helios + cells (Supplementary Figure S1B). Expression of Helios, a member of the Ikaros family of zinc‐finger transcription factors, inhibits IL‐2 production and as such is critical to Treg‐suppressive function 12 . Notably, the percentage of Helios + cells in each fraction corresponds inversely to the percentage of IL‐2 + cells reported by Miyara et al 11 We also confirmed that FrIII possessed the greatest proportion of CD161 + Th17‐like cells (Supplementary Figure S1C), a phenotype associated with IL‐17 production and loss of suppressive activity under inflammatory conditions 13 , 14 .…”

Section: Resultsmentioning

confidence: 99%

Altered regulatory T‐cell fractions and Helios expression in clinically isolated syndrome: clues to the development of multiple sclerosis

et al. 2017

View full text Add to dashboard Cite

Development of multiple sclerosis (MS) is frequently preceded by an acute or subacute neurological disturbance referred to as clinically isolated syndrome (CIS). The specific immunological disturbances present in CIS remain underexamined. This study analysed peripheral blood mononuclear cells from n=18 treatment-naive individuals with recently diagnosed CIS (<120 days) for disturbances in the phenotype of T regulatory (Treg), follicular T regulatory (Tfr), T helper (Th), follicular T helper (Tfh) and B cells. Relative to healthy controls (n=19), CIS was associated with lower proportions of suppressive CD45RA+FoxP3lo Treg and Tfr cells and greater proportions of non-suppressive CD45RA−FoxP3lo and Th17-like Treg and Tfr. Lower Helios expression (maen fluorescent intensity) was measured across all Treg and Tfr fractions in the CIS group, suggesting less potent regulatory function. Greater frequencies of activated, efficient B-cell helper Tfh subsets and a trend for a higher proportion of IgD−CD27− B cells was also detected in the CIS group, characteristics that were positively correlated with Treg and Tfr Helios expression. These results indicate that Treg and Tfr impairment is an early feature in MS.

show abstract

“…Additionally, the IL-2 receptor alpha chain, CD25, is expressed on CD4 + T reg and LAP is associated with the functional activity of T reg through modulation of transforming growth factor (TGF)-β [7]. We then wanted to investigate FoxP3 and Helios, a member of the Ikaros family of zinc-finger proteins, previously reported to be associated with suppressive activity of T reg [8], expression in TIM-3 + and LAP + T cells. 1b).…”

Section: Activated Tim-3 + and Lap + T Cells Co-express Pd-1 But Timmentioning

confidence: 99%

Effect of pembrolizumab on CD4+CD25+, CD4+LAP+ and CD4+TIM-3+ T cell subsets

Toor

Nair

Pfister

et al. 2019

Clinical and Experimental Immunology

View full text Add to dashboard Cite

Tumor immune evasion involves the expansion of avidly proliferating immunosuppressive cells and inhibition of effector T cell proliferation. Immune checkpoints (IC) block the activation pathways of tumor-reactive T cells. IC pathways are often exploited by tumor cells to evade immune destruction, and blocking these pathways through IC inhibitors (ICI) has shown promising results in multiple malignancies. In this study, we investigated the effects of an ICI, pembrolizumab, on various T cell subsets in vitro. We compared the suppressive activity of CD4 + CD25 + regulatory T cells (conventional T reg ) with T cells expressing T cell immunoglobulin-3 + (TIM-3 + ) and latency-associated peptide (LAP) + T cells. We found that LAP-expressing T cells were more suppressive than conventional T reg , but TIM-3-expressing T cells were not suppressive. Our results show that pembrolizumab does not modulate functions of T reg and mediates its immunostimulatory effects via the release of effector T cells from sup-pression. These findings may assist in the development of agents designed to intervene in IC pathways to overcome T reg resistance to ICI.

show abstract

Helios, and not FoxP3, is the marker of activated Tregs expressing GARP/LAP

Cited by 81 publications

References 51 publications

In-vitro effect of pembrolizumab on different T regulatory cell subsets

In-vitro effect of pembrolizumab on different T regulatory cell subsets

Altered regulatory T‐cell fractions and Helios expression in clinically isolated syndrome: clues to the development of multiple sclerosis

Effect of pembrolizumab on CD4+CD25+, CD4+LAP+ and CD4+TIM-3+ T cell subsets

Contact Info

Product

Resources

About