CD8+ T cells that express CD4 on their surface (CD4dimCD8bright T cells) recognize an antigen-specific target, are detected in vivo, and can be productively infected by T-tropic HIV

Zloza, Andrew; Sullivan, Yvonne B.; Connick, Elizabeth; Landay, Alan; Al‐Harthi, Lena

doi:10.1182/blood-2002-07-1972

Cited by 59 publications

(68 citation statements)

References 37 publications

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“…Memory CD4 + T cells have been shown to be selectively infected in SIV and HIV [1,[40][41][42]. Combined these observations support our earlier data suggesting that DP T cells in the intestine are rapidly eliminated in early SIV infection due to their increased expression of viral co-receptors and their higher level of activation [1].Several investigators have described increased DP T cells in the blood of patients infected with various pathogens [2, 3,15,[43][44][45][46]. A few studies have examined the function of DP cells in humans [2, 3,15,43].…”

supporting

confidence: 83%

“…Several investigators have described increased DP T cells in the blood of patients infected with various pathogens [2, 3,15,[43][44][45][46]. A few studies have examined the function of DP cells in humans [2, 3,15,43].…”

Section: Cytokine Expression By Dp Cd4 + Cd8 + Cells In Blood and Gutmentioning

confidence: 99%

“…A few studies have examined the function of DP cells in humans [2, 3,15,43]. Antigen-specific cytotoxic and proliferation responses were first demonstrated using viral antigens such as .…”

Section: Cytokine Expression By Dp Cd4 + Cd8 + Cells In Blood and Gutmentioning

confidence: 99%

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Intestinal double‐positive CD4⁺CD8⁺ T cells are highly activated memory cells with an increased capacity to produce cytokines

2006

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Peripheral blood and intestinal CD4 + CD8 + double-positive (DP) T cells have been described in several species including humans, but their function and immunophenotypic characteristics are still not clearly understood. Here we demonstrate that DP T cells are abundant in the intestinal lamina propria of normal rhesus macaques (Macaca mulatta). Moreover, DP T cells have a memory phenotype and are capable of producing different and/or higher levels of cytokines and chemokines in response to mitogen stimulation compared to CD4 + single-positive T cells. Intestinal DP T cells are also highly activated and have higher expression of CCR5, which makes them preferred targets for simian immunodeficiency virus/HIV infection. Increased levels of CD69, CD25 and HLA-DR, and lower CD62L expression were found on intestinal DP T cells populations compared to CD4 + single-positive T cells. Collectively, these findings demonstrate that intestinal and peripheral blood DP T cells are effector cells and may be important in regulating immune responses, which distinguishes them from the immature DP cells found in the thymus. Finally, these intestinal DP T cells may be important target cells for HIV infection and replication due to their activation, memory phenotype and high expression of CCR5. IntroductionCD4 + CD8 + double positive (DP) T cells in the intestine have been shown to be a major early target in primary simian immunodeficiency virus (SIV) infection [1]. Rapid depletion of intestinal DP cells occurs faster and more profoundly than that of intestinal CD4 + singlepositive (SP) cells which we have previously correlated with increased levels of CCR5 expression on the former [1]. Although DP T cells have been described in the blood and intestine of humans, nonhuman primates, swine and rodents [2][3][4][5][6][7][8][9][10][11][12], little is known regarding their function or immunophenotypic (naive versus memory status etc.) characteristics. DP T cells are perhaps best known in the thymus, where they are T cell precursors in early states of T cell maturation. However, DP T cells in the peripheral blood have been shown to differ from those in the thymus [2].Several investigators have reported the presence of circulating blood DP T cells, in both healthy [13,14] and diseased individuals [15][16][17][18][19][20][21][22]. Existence of this unconventional and rare lymphocyte population in peripheral blood has been hypothesized to result from premature release of immature CD4 + CD8 + T cells from the thymus to the periphery, where their maturation into functionally competent SP cell continues [23]. However, in HIV and Epstein-Barr virus infections, the percentage of DP T cells can increase to 20% of circulating lymphocytes, suggesting they are effector cells responding to infection [14,15]. In humans and animals DP T cells have also been shown to have antiviral activity, further suggesting they are indeed antigen-specific effector cells rather than immature cells from the thymus [2, 4,24]. The intestine is the major target organ of HIV...

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supporting

confidence: 83%

Section: Cytokine Expression By Dp Cd4 + Cd8 + Cells In Blood and Gutmentioning

confidence: 99%

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Intestinal double‐positive CD4⁺CD8⁺ T cells are highly activated memory cells with an increased capacity to produce cytokines

2006

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“…CD3 ϩ CD8 ϩ CD4 dim cells constitute a significant and often overlooked subpopulation of CD8 ϩ T cells in the peripheral blood (Fig. 1a) (7,8,10,43). The CD8 ϩ CD4 dim subset constitutes Ϸ5% of the CD3 ϩ CD8 ϩ population (Fig.…”

Section: Resultsmentioning

confidence: 99%

CD4 on CD8⁺T cells directly enhances effector function and is a target for HIV infection

Kitchen

Jones

LaForge

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Costimulation of purified CD8 ؉ T lymphocytes induces de novo expression of CD4, suggesting a previously unrecognized function for this molecule in the immune response. Here, we report that the CD4 molecule plays a direct role in CD8 ؉ T cell function by modulating expression of IFN-␥ and Fas ligand, two important CD8 ؉ T cell effector molecules. CD4 expression also allows infection of CD8 cells by HIV, which results in down-regulation of the CD4 molecule and impairs the induction of IFN-␥, Fas ligand, and the cytotoxic responses of activated CD8 ؉ T cells. Thus, the CD4 molecule plays a direct role in CD8 T cell function, and infection of these cells by HIV provides an additional reservoir for the virus and also may contribute to the immunodeficiency seen in HIV disease. C D8 ϩ cytotoxic T lymphocytes (CTL) have a major role in antiviral immunity, directly killing virally infected cells and producing antiviral cytokines. Activation of these cells requires interaction of the T cell receptor complex with antigenic peptide and major histocompatibility complex (MHC) class I molecules on antigen-presenting cells (APCs) followed by a second costimulatory signal (1). After activation, there is a coordinated expression of various cell surface molecules, many of which play a direct role in cytotoxic activity. We and others have shown that costimulation of CD8 ϩ T cells from the peripheral blood results in the de novo expression of CD4, a molecule previously thought to be absent on this cell type at this stage of development (2-5). These CD8 ϩ CD4 ϩ cells express higher levels of activation molecules than do costimulated CD8 ϩ T cells lacking CD4 expression (2, 6). CD8 ϩ CD4 ϩ T cells constitute Ϸ3-5% of the human peripheral blood lymphocyte pool (7-10). Certain conditions seem to influence CD8 ϩ CD4 ϩ cell levels in humans, including infection with HIV (11), human T lymphotrophic virus-1 (12), Epstein-Barr virus (8), human herpesvirus 6 (13), and aging (10). CD8 ϩ CD4 ϩ cells also have been observed in monkeys (14-17), and in mice, rats, swine, and chickens (reviewed in ref. 18). In mice, CD8 ϩ CD4 ϩ cell levels increased after inoculation with reovirus or recombinant adenovirus (19,20). In each species, the CD8 ϩ CD4 ϩ populations usually displayed the phenotype of activated or previously activated T cells and, in the studies that assessed the composition of the CD8 dimer, were predominantly CD8␣␤ (versus CD8␣␣) cells (11,15,19). The presence of CD8 ϩ CD4 ϩ cells in normal individuals and the increased representation of these cells in individuals with disease or increased antigenic stimulation suggest a role for this cell type in immunity.The CD4 molecule has an important role in CD4 ϩ T helper (Th) cell development and response to antigen, including functioning as an adhesion molecule, regulating cellular activation and gene expression, and serving as a chemotactic receptor (21-23). Its role as the primary receptor for HIV is well known (24,25). The cytoplasmic tail of the CD4 molecule on Th cells is associated with t...

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“…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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CD8+ T cells that express CD4 on their surface (CD4dimCD8bright T cells) recognize an antigen-specific target, are detected in vivo, and can be productively infected by T-tropic HIV

Cited by 59 publications

References 37 publications

Intestinal double‐positive CD4⁺CD8⁺ T cells are highly activated memory cells with an increased capacity to produce cytokines

Intestinal double‐positive CD4⁺CD8⁺ T cells are highly activated memory cells with an increased capacity to produce cytokines

CD4 on CD8⁺T cells directly enhances effector function and is a target for HIV infection

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

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CD8+ T cells that express CD4 on their surface (CD4dimCD8bright T cells) recognize an antigen-specific target, are detected in vivo, and can be productively infected by T-tropic HIV

Cited by 59 publications

References 37 publications

Intestinal double‐positive CD4+CD8+ T cells are highly activated memory cells with an increased capacity to produce cytokines

Intestinal double‐positive CD4+CD8+ T cells are highly activated memory cells with an increased capacity to produce cytokines

CD4 on CD8+T cells directly enhances effector function and is a target for HIV infection

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

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Intestinal double‐positive CD4⁺CD8⁺ T cells are highly activated memory cells with an increased capacity to produce cytokines

Intestinal double‐positive CD4⁺CD8⁺ T cells are highly activated memory cells with an increased capacity to produce cytokines

CD4 on CD8⁺T cells directly enhances effector function and is a target for HIV infection

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