Increased frequency of nonconventional double positive CD4CD8 αβ T cells in human breast pleural effusions

Desfrançois, Juliette; Derré, Laurent; Corvaisier, Murielle; Mevel, B. Le; Catros, Véronique; Jotereau, Francine; Gervois, Nadine

doi:10.1002/ijc.24366

Cited by 48 publications

(59 citation statements)

References 52 publications

(53 reference statements)

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“…6A). In contrast to previous studies that suggest that DP-T cells obtained from breast and melanoma cancer are able to produce IL-5 and IL-13 (16,17), in our study DP-T cells and SP-CD8 + T cells arising in the myelomainfiltrated bones did not express IL-5, IL-13, or IL-2 (data not shown). Both DP-T cells and SP-CD8 + T cells arising in the myeloma-infiltrated bones included degranulated CD107a + T cells, indicative of their ability to secrete perforin (18,19).…”

Section: Dp-t Cells and Sp-t Cells Arising In Myeloma-infiltrated Boncontrasting

confidence: 99%

“…This extends data from several other studies, suggesting that DP-T cells are accumulated in target organs of various diseases, such as the thyroid gland in patients with autoimmune thyroiditis (25), the skin of patients with atopic dermatitis and systemic sclerosis (26,27), and the joint fluid of patients with rheumatoid arthritis (28). In addition, DP-T cells have been reported in patients with cancer (16,17,29) and infectious diseases (30,31), and in allogeneic hematopoietic stem cell transplant recipients (32). The vast majority of DP-T cells arising in myeloma-infiltrated bones converted CD8ab heterodimer (expressed on SP-CD8 + T N prior to adoptive transfer into myeloma-bearing mice) to CD8aa homodimer.…”

Section: Discussionsupporting

confidence: 86%

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Myeloma-Induced Alloreactive T Cells Arising in Myeloma-Infiltrated Bones Include Double-Positive CD8+CD4+ T Cells: Evidence from Myeloma-Bearing Mouse Model

Freeman

Lam

Petcu

et al. 2011

The Journal of Immunology

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The graft-versus-myeloma (GVM) effect represents a powerful form of immune attack exerted by alloreactive T cells against multiple myeloma cells, which leads to clinical responses in multiple myeloma transplant recipients. Whether myeloma cells are themselves able to induce alloreactive T cells capable of the GVM effect is not defined. Using adoptive transfer of T naive cells into myeloma-bearing mice (established by transplantation of human RPMI8226-TGL myeloma cells into CD122+ cell-depleted NOD/SCID hosts), we found that myeloma cells induced alloreactive T cells that suppressed myeloma growth and prolonged survival of T cell recipients. Myeloma-induced alloreactive T cells arising in the myeloma-infiltrated bones exerted cytotoxic activity against resident myeloma cells, but limited activity against control myeloma cells obtained from myeloma-bearing mice that did not receive T naive cells. These myeloma-induced alloreactive T cells were derived through multiple CD8+ T cell divisions and enriched in double-positive (DP) T cells coexpressing the CD8αα and CD4 coreceptors. MHC class I expression on myeloma cells and contact with T cells were required for CD8+ T cell divisions and DP-T cell development. DP-T cells present in myeloma-infiltrated bones contained a higher proportion of cells expressing cytotoxic mediators IFN-γ and/or perforin compared with single-positive CD8+ T cells, acquired the capacity to degranulate as measured by CD107 expression, and contributed to an elevated perforin level seen in the myeloma-infiltrated bones. These observations suggest that myeloma-induced alloreactive T cells arising in myeloma-infiltrated bones are enriched with DP-T cells equipped with cytotoxic effector functions that are likely to be involved in the GVM effect.

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Section: Dp-t Cells and Sp-t Cells Arising In Myeloma-infiltrated Boncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 86%

Myeloma-Induced Alloreactive T Cells Arising in Myeloma-Infiltrated Bones Include Double-Positive CD8+CD4+ T Cells: Evidence from Myeloma-Bearing Mouse Model

Freeman

Lam

Petcu

et al. 2011

The Journal of Immunology

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“…To date, the lack of unequivocal studies prevents the establishment of a consensus regarding DP T-cell origin, phenotype and function for a given pathological context. Thus, DP T cells require individual consideration on a case-by-case basis.In cancer, DP T cells have been initially reported in lymphomas as cutaneous T-cell lymphomas [26][27][28] and nodular lymphocyte predominant Hodgkin lymphoma [29] where they were described as a CD4 high CD8 low DP T-cell population with cytotoxic activity [26].Besides, we documented the presence of CD4 low CD8αβ high DP T cells at a high frequency, among tumor-infiltrating lymphocytes (TILs) of several solid human tumors (breast carcinomas, melanomas, and colorectal carcinomas) [25,30,31]. Moreover, the prevalence of DP T cells in distant cutaneous metastasis was significantly higher (p < 0.05) than in lymph node metastasis and even higher (p < 0.01) than in blood from patients or healthy donors, suggesting an association between DP T-cell frequency and both tumor microenvironment and cancer progression.…”

mentioning

confidence: 62%

“…Besides, we documented the presence of CD4 low CD8αβ high DP T cells at a high frequency, among tumor-infiltrating lymphocytes (TILs) of several solid human tumors (breast carcinomas, melanomas, and colorectal carcinomas) [25,30,31]. Moreover, the prevalence of DP T cells in distant cutaneous metastasis was significantly higher (p < 0.05) than in lymph node metastasis and even higher (p < 0.01) than in blood from patients or healthy donors, suggesting an association between DP T-cell frequency and both tumor microenvironment and cancer progression.…”

Section: Introductionmentioning

confidence: 99%

IL‐9 promotes the survival and function of human melanoma‐infiltrating CD4⁺CD8⁺ double‐positive T cells

et al. 2016

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We previously demonstrated an accumulation of tumor-reactive CD4 + CD8 + double positive (DP) T cells within melanoma-infiltrating lymphocytes, supporting their role in the regulation of anti-tumor immune responses. Similarly to their CD8 + counterparts, intratumor DP T cells are MHC class-I restricted but differed by a limited lytic activity against autologous melanoma cells. Based on these observations and to further characterize DP T cells, both populations were compared at the transcriptional level. Our results revealed the overexpression of the IL-9 receptor (IL-9R) by DP T cells and prompted us to investigate the impact of IL-9 on their biology. We show that IL-9 favors DP T-cell survival by protecting them from apoptosis and by promoting their proliferation. In addition, IL-9 enhances their ability to produce cytokines and increased their levels of granzyme B/perforin as well as degranulation capacity, leading to a strengthened cytotoxic activity against melanoma cells. Taken together, the IL-9R high DP T-cell population could be a new preferential target for IL-9, which could take part in their retention within the melanoma infiltrate while also favoring their anti-tumor activity. More generally, our results extend the pleiotropic effects of IL-9 to IL-9R-expressing intra-tumor T cells, which could further potentiate anti-tumor immune responses.Keywords: CD4 + CD8 + double-positive T lymphocyte r IL-9R r IL-9 r Melanoma r TIL Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Nadine Gervois e-mail: nadine.gervois@inserm.fr IntroductionPeripheral CD4 + CD8 + double-positive (DP) T cells were first identified 25 years ago as a mature T-cell subpopulation accounting for about 1-2% of total T cells within healthy donor PBMCs Eur. J. Immunol. 2016Immunol. . 46: 1770Immunol. -1782 Tumor immunology 1771 with age-dependent increase [2]. Since then, DP T cells have been described as a highly heterogeneous population with at least three subsets based on the expression levels of the CD4 and the CD8 coreceptors (CD4 high CD8 low , CD4 low CD8 high , CD4 high CD8 high ) and on the nature of the CD8 dimer (αα or αβ) [3]. Regarding DP T cells lineage origin, two main hypotheses are still in debate. Some studies argued they step from a premature release of DP T cells from the thymus into the periphery, where their maturation into functionally competent single-positive (SP) cells continues [4,5].Others studies hypothesized that they could derive from peripheral single positive T cells. As such, IL-4 represents an important mediator of CD8αα induction on human SP CD4 T cells [6]. On the other hand, when activated in vitro via TCR cross-linking, SP CD8αβ T cells may become capable of expressing low levels of CD4 [7,8].Of interest, numerous studies reported the presence of DP T cells with, in most cases, an increased frequency in the blood and/or in the target organ of several pathological conditions (for review see [9]), such as autoimmune ...

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“…In contrast, CD4 high /CD8 high T cells are more likely to be Ag-specific effector cells, rather than immature cells released from the thymus. Indeed, such cells have been described to exert antiviral and antitumor immunity following contact with the cognate Ag (40)(41)(42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

Isolation of Human CD4/CD8 Double-Positive, Graft-Versus-Host Disease–Protective, Minor Histocompatibility Antigen–Specific Regulatory T Cells and of a Novel HLA-DR7–Restricted HY-Specific CD4 Clone

Eljaafari

Yuruker

Ferrand

et al. 2013

The Journal of Immunology

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Minor histocompatibility (H) Ags are classically described as self-peptides derived from intracellular proteins that are expressed at the cell surface by MHC class I and class II molecules and that induce T cell alloresponses. We have isolated three different T cell populations from a skin biopsy of a patient suffering from acute graft-versus-host disease following sex-mismatched HLA-identical bone marrow transplantation. The first population was: 1) CD4+/CD8+ double-positive; 2) specific for an HLA class I–restricted autosomal Ag; 3) expressed a Tr1 profile with high levels of IL-10, but low IL-2 and IFN-γ; and 4) exerted regulatory function in the presence of recipient APCs. The second was CD8 positive, specific for an HLA class I–restricted autosomally encoded minor H Ag, but was only weakly cytotoxic. The third was CD4 single positive, specific for an HLA-DR7–restricted HY epitope and exerted both proliferative and cytotoxic functions. Identification of the peptide recognized by these latter cells revealed a new human HY epitope, TGKIINFIKFDTGNL, encoded by RPS4Y and restricted by HLA-DR7. In this paper, we show human CD4/CD8 double-positive, acute graft-versus-host disease–protective, minor H Ag–specific regulatory T cells and identify a novel HLA-DR7/ HY T cell epitope, encoded by RPS4Y, a potential new therapeutic target.

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Increased frequency of nonconventional double positive CD4CD8 αβ T cells in human breast pleural effusions

Cited by 48 publications

References 52 publications

Myeloma-Induced Alloreactive T Cells Arising in Myeloma-Infiltrated Bones Include Double-Positive CD8+CD4+ T Cells: Evidence from Myeloma-Bearing Mouse Model

Myeloma-Induced Alloreactive T Cells Arising in Myeloma-Infiltrated Bones Include Double-Positive CD8+CD4+ T Cells: Evidence from Myeloma-Bearing Mouse Model

IL‐9 promotes the survival and function of human melanoma‐infiltrating CD4⁺CD8⁺ double‐positive T cells

Isolation of Human CD4/CD8 Double-Positive, Graft-Versus-Host Disease–Protective, Minor Histocompatibility Antigen–Specific Regulatory T Cells and of a Novel HLA-DR7–Restricted HY-Specific CD4 Clone

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Increased frequency of nonconventional double positive CD4CD8 αβ T cells in human breast pleural effusions

Cited by 48 publications

References 52 publications

Myeloma-Induced Alloreactive T Cells Arising in Myeloma-Infiltrated Bones Include Double-Positive CD8+CD4+ T Cells: Evidence from Myeloma-Bearing Mouse Model

Myeloma-Induced Alloreactive T Cells Arising in Myeloma-Infiltrated Bones Include Double-Positive CD8+CD4+ T Cells: Evidence from Myeloma-Bearing Mouse Model

IL‐9 promotes the survival and function of human melanoma‐infiltrating CD4+CD8+ double‐positive T cells

Isolation of Human CD4/CD8 Double-Positive, Graft-Versus-Host Disease–Protective, Minor Histocompatibility Antigen–Specific Regulatory T Cells and of a Novel HLA-DR7–Restricted HY-Specific CD4 Clone

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IL‐9 promotes the survival and function of human melanoma‐infiltrating CD4⁺CD8⁺ double‐positive T cells