CD4+CD8dim T lymphocytes exhibit enhanced cytokine expression, proliferation and cytotoxic activity in response to HCMV and HIV-1 antigens

Suni, Maria; Ghanekar, Smita; Houck, David W.; Maecker, Holden T.; Wormsley, Susan B.; Picker, Louis J.; Moss, Ronald B.; Maino, Vernon C.

doi:10.1002/1521-4141(200108)31:8<2512::aid-immu2512>3.0.co;2-m

Cited by 108 publications

(109 citation statements)

References 34 publications

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“…2C). DP T cells have been described previously [9][10][11][12][13], with CD4 bright CD8 dim DP T cells arising from the up-regulation of CD8 expression by CD4 + T cells [9,13]. Surprisingly, we found that this population of T cells expresses very high levels of PD-1 in both infected and uninfected monkeys ( Fig.…”

Section: Chronic Infection Increases Pd-1 Expressionsupporting

confidence: 73%

Activation drives PD‐1 expression during vaccine‐specific proliferation and following lentiviral infection in macaques

et al. 2008

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Recent data supports that increased expression of PD-1, a negative regulator of immune function, is associated with T cell exhaustion during chronic viral infection. However, PD-1 expression during acute infection and vaccination has not been studied in great detail in primates. Here, we examine PD-1 expression on CD3 + T cells following DNA vaccination or lentiviral infection of macaques. Ex vivo peptide stimulation of PBMC from DNA-vaccinated uninfected macaques revealed a temporal increase in PD-1 expression in proliferating antigen-specific CD8 + T cells. Following the initial increase, PD-1 expression steadily declined as proliferation continued, with a concomitant increase in IFN-c secretion. Subsequent examination of PD-1 expression on T cells from uninfected and lentivirusinfected non-vaccinated macaques revealed a significant increase in PD-1 expression with lentiviral infection, consistent with previous reports. PD-1 expression was highest on cells with activated memory and effector phenotypes. Despite their decreased telomere length, PD-1 hi T cell populations do not appear to have statistically significant uncapped telomeres, typically indicative of proliferative exhaustion, suggesting a different mechanistic regulation of proliferation by PD-1. Our data indicate that PD-1 expression is increased as a result of T cell activation during a primary immune response as well as during persistent immune activation in macaques.

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Section: Chronic Infection Increases Pd-1 Expressionsupporting

confidence: 73%

Activation drives PD‐1 expression during vaccine‐specific proliferation and following lentiviral infection in macaques

et al. 2008

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“…Over the past 2 decades, the ability of CD4 ϩ T cells to display cytotoxic potential has been reported in isolated, but repeated, reports in both mouse and human (2)(3)(4)(5)(6). However, the observation of such cytotoxic activity in CD4 ϩ T cells has usually been restricted to cell lines and CD4 ϩ T cell clones generated by long term in vitro culture and has therefore been considered by some authors to be an artifact (7).…”

Section: T He Cd4mentioning

confidence: 99%

“…It forms pores in target cell membranes, enabling the entry of granzymes that activate an apoptotic cascade resulting in cell death (13,14). The expression of perforin and granzymes is usually said to be restricted to circulating CD8 ϩ T cells and NK cells (15), but has recently also been shown in CD4 ϩ CD8 ϩ double-positive T cells (6).…”

Section: T He Cd4mentioning

confidence: 99%

Characterization of CD4+ CTLs Ex Vivo

Appay

Zaunders

Papagno

et al. 2002

The Journal of Immunology

481

460

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The cytotoxic potential of CD8+ T cells and NK cells plays a crucial role in the immune response to pathogens. Although in vitro studies have reported that CD4+ T cells are also able to mediate perforin-mediated killing, the in vivo existence and relevance of cytotoxic CD4+ T cells have been the subject of debate. Here we show that a population of CD4+ perforin+ T cells is present in the circulation at low numbers in healthy donors and is markedly expanded in donors with chronic viral infections, in particular HIV infection, at all stages of the disease, including early primary infection. Ex vivo analysis shows that these cells have cytotoxic potential mediated through the release of perforin. In comparison with more classical CD4+ T cells, this subset displays a distinct surface phenotype and functional profile most consistent with end-stage differentiated T cells and include Ag experienced CD4+ T cells. The existence of CD4+ cytotoxic T cells in vivo at relatively high levels in chronic viral infection suggests a role in the immune response.

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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%

“…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]. 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.…”

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+CD8dim T lymphocytes exhibit enhanced cytokine expression, proliferation and cytotoxic activity in response to HCMV and HIV-1 antigens

Cited by 108 publications

References 34 publications

Activation drives PD‐1 expression during vaccine‐specific proliferation and following lentiviral infection in macaques

Activation drives PD‐1 expression during vaccine‐specific proliferation and following lentiviral infection in macaques

Characterization of CD4+ CTLs Ex Vivo

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

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CD4+CD8dim T lymphocytes exhibit enhanced cytokine expression, proliferation and cytotoxic activity in response to HCMV and HIV-1 antigens

Cited by 108 publications

References 34 publications

Activation drives PD‐1 expression during vaccine‐specific proliferation and following lentiviral infection in macaques

Activation drives PD‐1 expression during vaccine‐specific proliferation and following lentiviral infection in macaques

Characterization of CD4+ CTLs Ex Vivo

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

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