Clonal Expansions of CD8+ T Cells with IL-10 Secreting Capacity Occur during Chronic Mycobacterium tuberculosis Infection

Cyktor, Joshua C.; Carruthers, Bridget; Beamer, Gillian; Turner, Joanne

doi:10.1371/journal.pone.0058612

Cited by 33 publications

(28 citation statements)

References 63 publications

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“…Since we observed negligible secretion of IL‐10 by CTLs reactivated under AtO 2 , our results suggest that this capacity of CTLs is underestimated by conventional in vitro methodology, but will likely occur in vivo in many tissues, as we observed for il10 ‐expressing CD8 + TILs. In the limited number of reports concerning IL‐10 production by CD8 + T cells that we are aware of, most have been in the context of infection: coronavirus‐induced acute encephalitis, chronic mycobacterium tuberculosis infection, and respiratory viral infection . CTL‐produced IL‐10 has been suggested as a feedback mechanism to dampen immunopathology caused by excessive cytolytic and inflammatory activity .…”

Section: Discussionmentioning

confidence: 99%

Phenotypic switch of CD8⁺ T cells reactivated under hypoxia toward IL‐10 secreting, poorly proliferative effector cells

et al. 2015

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CD8+ T cells controlling pathogens or tumors must function at sites where oxygen tension is frequently low, and never as high as under atmospheric culture conditions. However, T-cell function in vivo is generally analyzed indirectly, or is extrapolated from in vitro studies under nonphysiologic oxygen tensions. In this study, we delineate the role of physiologic and pathologic oxygen tension in vitro during reactivation and differentiation of tumor-specific CD8 + T cells. Using CD8 + T cells from pmel-1 mice, we observed that the generation of CTLs under 5% O 2 , which corresponds to physioxia in lymph nodes, gave rise to a higher effector signature than those generated under atmospheric oxygen fractions (21% O 2 ). Hypoxia (1% O 2 ) did not modify cytotoxicity, but decreasing O 2 tensions during CTL and CD8 + tumor-infiltrating lymphocyte reactivation dose-dependently decreased proliferation, induced secretion of the immunosuppressive cytokine IL-10, and upregulated the expression of CD137 (4-1BB) and CD25. Overall, our data indicate that oxygen tension is a key regulator of CD8 + T-cell function and fate and suggest that IL-10 release may be an unanticipated component of CD8 + T cell-mediated immune responses in most in vivo microenvironments. Keywords: CD8+ T cell r Oxygen r Hypoxia r IL-10 r T-cell reactivation Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIn a healthy physiologic context, oxygen tensions in mammalian tissues are tightly regulated, but still show significant variation both between tissues and within the same tissue (Supporting Information Fig. 1A) [1][2][3]. However, oxygen tensions are far below physiologic values in different pathologic conditions, mostly involving inflammation [4], solid tumors [5,6], and infections [7]. In contrast to sufficient oxygen supply (i.e. normoxia), oxygen deprivation (i.e. hypoxia) leads to cellular responses involving Correspondence: Dr. Paul R. Walker e-mail: Paul.Walker@hcuge.ch stabilization of HIFs (hypoxia-inducible factors), transcription factors that are composed of an inducible α-subunit (i.e. HIF-1α, HIF-2α, or HIF-3α) together with a constitutive β-subunit (i.e. HIF-1β, HIF-2β, or HIF-3β) [8]. Upon stabilization, HIFs transcribe various genes with HIF-responsive elements in their promoter; these include those that increase angiogenesis (e.g. VEGF) and glucose metabolism (e.g. glucose transporters) [9]. Interestingly, HIF-1α and HIF-2α can have unique, redundant, or opposing roles [9,10]. Furthermore, while HIF-1α is described to be stabilized and active below 2% O 2 in an acute manner, HIF-2α has been shown to be stable below 5% O 2 in a chronic manner [11,12]. However, although HIFs are central to many hypoxia responses, certain effects have been shown to be HIF-independent [13][14][15]. Intriguingly, HIF-1α can also be involved in immune cell activation Eur. J. Immunol. 2015Immunol. . 45: 2263Immunol. -2275 under atmospheric oxygen fractions (AtO 2 ; i.e. 21%), as rep...

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Section: Discussionmentioning

confidence: 99%

Phenotypic switch of CD8⁺ T cells reactivated under hypoxia toward IL‐10 secreting, poorly proliferative effector cells

et al. 2015

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“…Importantly, engagement of IL-10R by either the cIL-10 or vIL-10 ligand appears to be a virulence factor for pathogenic infections or a requisite step for commensal bacterial infections (5). Multiple approaches have been employed to demonstrate that abrogation of cIL-10 induction and signaling attenuates infection and/or disease of bacteria (31)(32)(33)(34)(35)(36)(37)(38)(39), fungi (40), and viruses (9,18,(41)(42)(43). Based on the premise that microbial manipulation of IL-10 signaling confers greater replication fitness in the infected host, targeted disruption of microbial exploitation of IL-10 signaling offers a clinically relevant option for preventing primary infection or reducing viral sequelae.…”

Section: Discussionmentioning

confidence: 99%

Vaccination against a Virus-Encoded Cytokine Significantly Restricts Viral Challenge

Eberhardt

Deshpande

Chang

et al. 2013

J Virol

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T here is ample precedent from studies of licensed viral and microbial vaccines that vaccine-mediated stimulation of pathogen-specific B cell immunity is critical for protection from infection and/or disease (1). Many new vaccine designs are predicated on the induction of antibodies that neutralize viral attachment to susceptible cells. As phase 2 clinical trials on human cytomegalovirus (HCMV) vaccination have shown, however, this approach only partially protects against challenge virus infection. In one study, seronegative women who had given birth within the previous year were vaccinated against HCMV glycoprotein B (gB) (2), the predominant virion target for antibodies that neutralize infection of fibroblasts. While significant protection against primary HCMV infection was observed in the vaccine group, the effect was limited in magnitude (50%) and duration. In the second placebocontrolled, randomized study, liver and kidney transplant candidates were similarly immunized with gB and prospectively evaluated for parameters of HCMV infection posttransplantation (3). Vaccine-mediated increases in gB-specific antibody titers were inversely correlated with the duration of HCMV viremia posttransplantation. Similar to the trial involving seronegative women, however, vaccination against gB alone in transplant recipients did not completely protect those at risk for HCMV infection.

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“…In CBA/J mice (which are more susceptible than other mouse strains), CD8 T cells expressing PD-1, Tim-3 or CD122 were able to produce IL10, resulting in greater susceptibility to chronic M. tuberculosis infection (67). These data suggest that CD8 may play an important role in the regulating the immune response.…”

Section: Potential Regulatory Roles Of Cd8 T Cellsmentioning

confidence: 99%

CD8 T cells and Mycobacterium tuberculosis infection

2015

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Tuberculosis is primarily a respiratory disease that is caused by Mycobacterium tuberculosis. M. tuberculosis can persist and replicate in macrophages in vivo, usually in organized cellular structures called granulomas. There is substantial evidence for the importance of CD4 T cells in control of tuberculosis, but the evidence for a requirement for CD8 T cells in this infection has not been proven in humans. However, animal model data support a non-redundant role for CD8 T cells in control of M. tuberculosis infection, and in humans, infection with this pathogen leads to generation of specific CD8 T cell responses. These responses include classical (MHC Class I restricted) and non-classical CD8 T cells. Here, we discuss the potential roles of CD8 T cells in defense against tuberculosis, and our current understanding of the wide range of CD8 T cell types seen in M. tuberculosis infection.

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Clonal Expansions of CD8+ T Cells with IL-10 Secreting Capacity Occur during Chronic Mycobacterium tuberculosis Infection

Cited by 33 publications

References 63 publications

Phenotypic switch of CD8⁺ T cells reactivated under hypoxia toward IL‐10 secreting, poorly proliferative effector cells

Phenotypic switch of CD8⁺ T cells reactivated under hypoxia toward IL‐10 secreting, poorly proliferative effector cells

Vaccination against a Virus-Encoded Cytokine Significantly Restricts Viral Challenge

CD8 T cells and Mycobacterium tuberculosis infection

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Clonal Expansions of CD8+ T Cells with IL-10 Secreting Capacity Occur during Chronic Mycobacterium tuberculosis Infection

Cited by 33 publications

References 63 publications

Phenotypic switch of CD8+ T cells reactivated under hypoxia toward IL‐10 secreting, poorly proliferative effector cells

Phenotypic switch of CD8+ T cells reactivated under hypoxia toward IL‐10 secreting, poorly proliferative effector cells

Vaccination against a Virus-Encoded Cytokine Significantly Restricts Viral Challenge

CD8 T cells and Mycobacterium tuberculosis infection

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Product

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Phenotypic switch of CD8⁺ T cells reactivated under hypoxia toward IL‐10 secreting, poorly proliferative effector cells

Phenotypic switch of CD8⁺ T cells reactivated under hypoxia toward IL‐10 secreting, poorly proliferative effector cells