Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells

Duhen, Thomas; Duhen, Rebekka; Lanzavecchia, Antonio; Sallusto, Federica; Campbell, Daniel

doi:10.1182/blood-2011-11-392324

Cited by 358 publications

(409 citation statements)

References 51 publications

(68 reference statements)

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“…The correlation between the frequencies of Ki67 1 CD25 1 Foxp3 1 CD4 T cells and cytokine-producing CD4 T cells 7 days post-vaccination are consistent with previous studies reporting accumulation of Tregs in parallel with effector CD4 T cells at sites of infection (24,25). Moreover, they are consistent with recent studies reporting parallel functional specialization of Treg and effector CD4 T-cell populations in humans (26). In clinical trials of the TB vaccine MVA85A, a positive correlation was observed between the frequency of prevaccination purified protein derivative-specific IFN-gproducing cells and the frequency of CD25 hi CD39 1 CD4 T cells in adults prevaccination and post-vaccination (27), thus further underscoring the important interplay between regulatory and effector immune responses induced after vaccination.…”

Section: Discussionsupporting

confidence: 81%

Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults

Day

Tameris

Mansoor

et al. 2013

Am J Respir Crit Care Med

106

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Rationale: Tuberculosis (TB) is a major cause of morbidity and mortality worldwide, thus there is an urgent need for novel TB vaccines. Objectives: We investigated a novel TB vaccine candidate, M72/ AS01, in a phase IIa trial of bacille Calmette-Gué rin-vaccinated, HIV-uninfected, and Mycobacterium tuberculosis (Mtb)-infected and -uninfected adults in South Africa. Methods: Two doses of M72/AS01 were administered to healthy adults, with and without latent Mtb infection. Participants were monitored for 7 months after the first dose; cytokine production profiles, cell cycling, and regulatory phenotypes of vaccine-induced T cells were measured by flow cytometry. Measurements and Main Results: The vaccine had a clinically acceptable safety profile, and induced robust, long-lived M72-specific T-cell and antibody responses. M72-specific CD4 T cells produced multiple combinations of Th1 cytokines. Analysis of T-cell Ki67 expression showed that most vaccination-induced T cells did not express Th1 cytokines or IL-17; these cytokine-negative Ki67 1 T cells included subsets of CD4 T cells with regulatory phenotypes. PD-1, a negative regulator of activated T cells, was transiently expressed on M72-specific CD4 T cells after vaccination. Specific T-cell subsets were present at significantly higher frequencies after vaccination of Mtb-infected versus -uninfected participants. Conclusions: M72/AS01 is clinically well tolerated in Mtb-infected and -uninfected adults, induces high frequencies of multifunctional T cells, and boosts distinct T-cell responses primed by natural Mtb infection. Moreover, these results provide important novel insights into how this immunity may be appropriately regulated after novel TB vaccination of Mtb-infected and -uninfected individuals. Clinical trial registered with www.clinicaltrials.gov (NCT 00600782).Keywords: tuberculosis; vaccine; T cell; cytokine; proliferation Tuberculosis (TB) remains a major cause of morbidity and mortality, with approximately 9 million new cases and 1.5 million deaths worldwide each year (1). Bacille Calmette-Guérin (BCG) provides protection against miliary TB and TB meningitis in children (2); however, BCG provides variable efficacy against pulmonary TB in adults (3), the most common clinical manifestation of the disease. Mycobacterium tuberculosis (Mtb) is transmitted primarily by adults; therefore novel, effective TB vaccines are urgently needed to target this population, and thereby reduce the burden of TB disease worldwide.Phase I and II clinical trials of several novel candidate TB vaccines have either been completed or are currently ongoing (4). These vaccines include the candidate recombinant fusion protein vaccine M72, formulated with GlaxoSmithKline Vaccines Approximately one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), and despite the widespread use of the bacille Calmette-Guérin vaccine, tuberculosis (TB) remains a major cause of morbidity and mortality. There is an urgent need to develop novel TB vaccines that are safe,...

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Section: Discussionsupporting

confidence: 81%

Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults

Day

Tameris

Mansoor

et al. 2013

Am J Respir Crit Care Med

106

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“…RORC was higher in the CCR6 + subsets and lower in the CCR6 2 subsets, a pattern consistent with that in Teff cells (22). TBX21 showed higher expression in the CXCR3 + subsets and lower in the CXCR3 2 subsets, as has been reported (11,16). Strikingly, GATA3 expression was the highest in the CCR6 2 CXCR3 2 subset and lowest in the CCR6 + CXCR3 + subset.…”

Section: Gene Expression Profiling Identifies Five Major Subgroups Ofsupporting

confidence: 72%

“…In humans, the heterogeneity of Treg cell subpopulations in the PBMCs has been documented, typically focusing on cell surface molecules expressed on Th cells (14)(15)(16)(17). However, the overall extent of diversity, the degree of overlap between cell surface molecules, and how many of them represent reasonably distinct subpopulations (e.g., specific gene expression patterns or functions) are not clear.…”

Section: R Egulatory T (Treg) Cells Play a Key Role In Maintainingmentioning

confidence: 99%

Diverse Gene Expression in Human Regulatory T Cell Subsets Uncovers Connection between Regulatory T Cell Genes and Suppressive Function

Hua

Davis

Hill

et al. 2015

The Journal of Immunology

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Regulatory T (Treg) cells have a critical role in the control of immunity, and their diverse subpopulations may allow adaptation to different types of immune responses. In this study, we analyzed human Treg cell subpopulations in the peripheral blood by performing genome-wide expression profiling of 40 Treg cell subsets from healthy donors. We found that the human peripheral blood Treg cell population is comprised of five major genomic subgroups, represented by 16 tractable subsets with a particular cell surface phenotype. These subsets possess a range of suppressive function and cytokine secretion and can exert a genomic footprint on target effector T (Teff) cells. Correlation analysis of variability in gene expression in the subsets identified several cell surface molecules associated with Treg suppressive function, and pharmacological interrogation revealed a set of genes having causative effect. The five genomic subgroups of Treg cells imposed a preserved pattern of gene expression on Teff cells, with a varying degree of genes being suppressed or induced. Notably, there was a cluster of genes induced by Treg cells that bolstered an autoinhibitory effect in Teff cells, and this induction appears to be governed by a different set of genes than ones involved in counteracting Teff activation. Our work shows an example of exploiting the diversity within human Treg cell subpopulations to dissect Treg cell biology.

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“…In humans, the FOXP3 gene was shown to be affected in the severe autoimmune condition IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome) (Ref. 16 54,72,73,74,75). The frequency of cytokine-producing Treg can be increased by cytokine treatments.…”

Section: Introductionmentioning

confidence: 99%

T regulatory cells in childhood arthritis – novel insights

Pesenacker

Wedderburn

2013

Expert Rev. Mol. Med.

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In recent years, there have been many new developments in the field of regulatory T cells (Treg), challenging the consensus on their behaviour, classification and role(s) in disease. The role Treg might play in autoimmune disease appears to be more complex than previously thought. Here, we discuss the current knowledge of regulatory T cells through animal and human research and illustrate the recent developments in childhood autoimmune arthritis (juvenile idiopathic arthritis (JIA)). Furthermore, this review summarises our understanding of the fields and assesses current and future implications for Treg in the treatment of JIA.

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Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells

Cited by 358 publications

References 51 publications

Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults

Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults

Diverse Gene Expression in Human Regulatory T Cell Subsets Uncovers Connection between Regulatory T Cell Genes and Suppressive Function

T regulatory cells in childhood arthritis – novel insights

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