CD4+/CD8+ double-positive T cells: more than just a developmental stage?

Overgaard, Nana Haahr; Jung, Ji‐Won; Steptoe, Raymond J.; Wells, James W.

doi:10.1189/jlb.1ru0814-382

Cited by 250 publications

(240 citation statements)

References 83 publications

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“…1 /CD8 1 DP T cells play a crucial role in various pathologies such as cancer and autoimmune disorders and Eljaafari et al studied their protective effects in GvHD (36,37). We also see CD4…”

Section: Discussionmentioning

confidence: 94%

Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ^−/− (NSG) mice by ex vivo modulation of human CD4⁺ T cells

et al. 2016

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NOD.Cg-Prkdcscid IL-2rg tm1Wjl /SzJ (NSG) mice are a valuable tool for studying Graftversus-Host-Disease (GvHD) induced by human immune cells. We used a model of acute GvHD by transfer of human peripheral blood mononuclear cells (PBMCs) into NSG mice. The severity of GvHD was reflected by weight loss and was associated with engraftment of human cells and the expansion of leukocytes, particularly granulocytes and monocytes. Pre-treatment of PBMCs with the anti-human CD4 antibody MAX.16H5 IgG1 or IgG4 attenuated GvHD. The transplantation of 2 3 10 7 PBMCs without anti-human CD4 pre-treatment induced a severe GvHD (0% survival). In animals receiving 2 3 10 7 PBMCs pre-incubated with MAX.16H5 IgG1 or IgG4, GvHD development was reduced and survival was increased. Immune reconstitution was measured by flow cytometry and confirmed for human leukocytes (CD45), CD3 /CD41 T helper cells. Human B cells (CD19) and monocytes (CD14) could not be detected. Histopathological analysis (TUNEL assay) of the gut of recipient animals showed significantly less apoptotic crypt cells in animals receiving a MAX.16H5 IgG1 pre-incubated graft. These findings indicate that preincubation of an allogeneic graft with an anti-human CD4 antibody may decrease the frequency and severity of GvHD after hematopoietic stem cell transplantation (HSCT) and the need of conventional immunosuppressive drugs. Moreover, this approach most probably provides a safer HSCT that must be confirmed in appropriate clinical trials in the future. V C 2016 International Society for Advancement of Cytometry

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Section: Discussionmentioning

confidence: 94%

Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ^−/− (NSG) mice by ex vivo modulation of human CD4⁺ T cells

et al. 2016

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“…Comparison of CD4:CD8 ratios in BAL of humans and macaques was confounded by the observation that DP T expressing both CD4 and CD8 were observed in BAL of macaques, but not of humans. DP T populations have been reported in multiple animal models (39)(40)(41) and in previous human studies (42)(43)(44). In humans, DP T have been described in the peripheral blood as differentiated antigen-specific cells developed in response to viral pathogens (44) and in the affected tissues of suspected autoimmune diseases (reviewed in Reference 39); DP T were also identified in BAL of HIV-infected patients with chronic obstructive pulmonary disease but not in HIV infection or chronic obstructive pulmonary disease alone (45).…”

Section: and Cd11cmentioning

confidence: 99%

Diversity of Human and Macaque Airway Immune Cells at Baseline and during Tuberculosis Infection

Silver

Myers

Jarvela

et al. 2016

Am J Respir Cell Mol Biol

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Immune cells of the distal airways serve as "first responders" of host immunity to the airborne pathogen Mycobacterium tuberculosis (Mtb). Mtb infection of cynomolgus macaques recapitulates the range of human outcomes from clinically silent latent tuberculosis infection (LTBI) to active tuberculosis of various degrees of severity. To further advance the application of this model to human studies, we compared profiles of bronchoalveolar lavage (BAL) cells of humans and cynomolgus macaques before and after Mtb infection. A simple gating strategy effectively defined BAL T-cell and phagocyte populations in both species. BAL from Mtb-naive humans and macaques showed similar differential cell counts. BAL T cells of macaques were composed of fewer CD41 cells but more CD81 and CD4 1 CD8 1 double-positive cells than were BAL T cells of humans. The most common mononuclear phagocyte population in BAL of both species displayed coexpression of HLA-DR, CD206, CD11b, and CD11c; however, multiple phagocyte subsets displaying only some of these markers were observed as well. Macaques with LTBI displayed a marked BAL lymphocytosis that was not observed in humans with LTBI. In macaques, the prevalence of specific mononuclear phagocyte subsets in baseline BAL correlated with ultimate outcomes of Mtb infection (i.e., LTBI versus active disease).Overall, these findings demonstrate the comparability of studies of pulmonary immunity to Mtb in humans and macaques. They also indicate a previously undescribed complexity of airway mononuclear phagocyte populations that suggests further lines of investigation relevant to understanding the mechanisms of both protection from and susceptibility to the development of active tuberculosis within the lung.

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“…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 diseases [10][11][12], inflammation disorders [13,14], allergies [15,16], infectious diseases [17][18][19], and cancer, postulating their involvement in pathologic events [20][21][22][23]. In these contexts, diverse functions of DP T cells were observed from cytotoxic activity [22,24] to regulatory properties [25], as well as helper potential [10].…”

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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CD4+/CD8+ double-positive T cells: more than just a developmental stage?

Cited by 250 publications

References 83 publications

Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ^−/− (NSG) mice by ex vivo modulation of human CD4⁺ T cells

Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ^−/− (NSG) mice by ex vivo modulation of human CD4⁺ T cells

Diversity of Human and Macaque Airway Immune Cells at Baseline and during Tuberculosis Infection

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

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CD4+/CD8+ double-positive T cells: more than just a developmental stage?

Cited by 250 publications

References 83 publications

Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ−/− (NSG) mice by ex vivo modulation of human CD4+ T cells

Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ−/− (NSG) mice by ex vivo modulation of human CD4+ T cells

Diversity of Human and Macaque Airway Immune Cells at Baseline and during Tuberculosis Infection

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

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Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ^−/− (NSG) mice by ex vivo modulation of human CD4⁺ T cells

Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ^−/− (NSG) mice by ex vivo modulation of human CD4⁺ T cells

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