Interleukin-21 Is a Critical Regulator of CD4 and CD8 T Cell Survival during Priming under Interleukin-2 Deprivation Conditions

Khattar, Mithun; Miyahara, Yoshihiro; Schroder, Paul M.; Xie, Anmu; Chen, Wenhao; Stepkowski, Stanislaw M.

doi:10.1371/journal.pone.0085882

Cited by 15 publications

(12 citation statements)

References 56 publications

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“…Data from our laboratory recently showed that IL-21 was up-regulated during the peak of the effector CD8 T cell immune response to E. cuniculi infection and absence of signaling for this cytokine led to impaired CD8 T cell immunity (manuscript under preparation). Our findings are supported by recent observations, which demonstrated that under IL-2 deprivation conditions, IL-21 might act as the major survival factor promoting the T cell immune response [53]. In addition, it has been reported that IL-21 can synergize with two other common gamma chain members, IL-7 and IL-15, in order to promote expansion and in some cases anti tumor functions of CD8 T cells [54,55].…”

Section: Role Of Cd4 Help In the Development Of Cd8 T Cell Immunity Asupporting

confidence: 90%

Effector CD8 T cell immunity in microsporidial infection: a lone defense mechanism

2015

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Microsporidia are a group of pathogens, which can pose severe risks to the immunocompromised population such as HIV infected individuals. The expertise to diagnose these pathogens is limited and therefore their prevalence is believed to be much higher than what is currently known. In a mouse model of infections, it has been reported that CD8 T cells are the primary effector cells responsible for protecting the infected host. As the infection is acquired via per-oral route, CD8 T cells in the gut compartment apparently act as a first line of defense against the pathogens. Thus, generation of a robust CD8 T cell response that exhibits polyfunctional ability is critical for host survival. In this review, we describe the effector CD8 T cells generated during microsporidial infection and underline the factors that may be essential for the elicitation of protective immunity against this understudied but significant pathogen. Overall, this review will highlight the necessity for a better understanding of the development of the CD8 T cell response in gut associated lymphoid tissue (GALT) and provide some insights into therapies that may be used to restore defective CD8 T cell functionality in an immunocompromised situation.

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Section: Role Of Cd4 Help In the Development Of Cd8 T Cell Immunity Asupporting

confidence: 90%

Effector CD8 T cell immunity in microsporidial infection: a lone defense mechanism

2015

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“…2G). Importantly, we did not observe a correlation between production of IL-2 by CD4 T cells and IL-21 by CD8 T cells (data not shown), unlike what was noted in mouse models, whereby limited IL-2 production was associated with increased IL-21 production by CD4 T cells (2,23). To ascertain whether IL-21-producing CD8 T cells manifested traits that resemble T follicular helper (Tfh) cells (24,25), we determined the frequency of IL-21-producing CD8 T cells that coexpressed Tfh-associated markers CXCR5 and inducible costimulator (ICOS).…”

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confidence: 52%

Immune Activation Is Associated with CD8 T Cell Interleukin-21 Production in HIV-1-Infected Individuals

Williams

Amatya

Bansal

et al. 2014

J Virol

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c Interleukin-21 (IL-21) can be produced by CD8 T cells from HIV-1-infected individuals and those with autoimmune disease, but the mechanism remains poorly understood. Here we demonstrate that IL-21-producing CD8 T cells are not associated with CD4 depletion and are absent in patients with idiopathic CD4 lymphocytopenia. Instead, IL-21 production by CD8 T cells was associated with high levels of activation, suggesting that these cells emerge as a consequence of excessive chronic immune activation rather than CD4 lymphopenia.A s a product of CD4 T cells, interleukin-21 (IL-21) has emerged as a key factor for control of chronic viral infections (1-8). Accumulating evidence suggests that CD8 T cells secrete IL-21, and populations of these cells have been described in HIV-1 infection and autoimmunity (9-13). We have demonstrated that HIV-1-specific IL-21-producing CD8 T cells are enriched in HIV-1 elite controllers, whereas polyclonally stimulated IL-21-producing CD8 T cells are increased in patients who lack viral control (12).The basis for the apparent division of IL-21 competency between CD4 and CD8 T cell subsets is unclear, but one possibility is that CD4-negative T cells may acquire CD4 T-helper function (14)(15)(16)(17)(18)(19)(20). Given that CD4 T cell depletion is a hallmark of HIV-1 infection, such a compensatory mechanism could allow for CD8 T cells to acquire IL-21 competency and helper function. On the other hand, CD8 T cell production of IL-21 could also be seen with immune perturbations such as seen in HIV-1 infection and autoimmunity, diseases associated with this unusual cellular phenotype (9-13).We sought to define IL-21-competent CD8 T cells and determine their relation to conventional CD4 T cells. Cryopreserved peripheral blood mononuclear cells (PBMCs) from 30 chronically HIV-1-infected individuals off antiretroviral therapy (ART) (median plasma viral load [pVL], 18,282 copies/ml; median CD4 count, 581 cells/mm 3 ) and 19 HIV-1-seronegative subjects were thawed, activated with phorbol 12,13-dibutyrate and ionomycin (PDBu and ionomycin), and stained as previously described (12). The institutional review boards (IRBs) of the University of Alabama at Birmingham (UAB) and National Institute of Allergy and Infectious Diseases (NIAID) approved this study, and written informed consent was obtained from study participants. ϩ CD8 Ϫ , CD4 ϩ CD8 ϩ , and CD4 Ϫ CD8 ϩ IL-21-producing T cells in HIV-1-infected subjects.

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“…Recent observations have shown that IL-21 was able to rescue CD8 T cells cultured under IL-2 deprivation conditions. In these studies, blockade of both IL-2 and IL-21 signaling pathway led to reduced CD8 T cell survival (38). Similarly, in another study, IL-21 alone promoted expansion and cytolytic development of OT1 T cells (39).…”

Section: Discussionmentioning

confidence: 99%

IL-21 Is Important for Induction of KLRG1+ Effector CD8 T Cells during Acute Intracellular Infection

Moretto

Khan

2016

The Journal of Immunology

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Microsporidia, a latent opportunistic infection associated with mild inflammation, is characterized by a strong CD8 T cell response, which has been shown to be CD4 T cell dependent. In this manuscript, we demonstrate for the first time that CD4 help is provided via IL-21 production, a common gamma chain cytokine closely related to IL-2. The peak of IL-21 expression, observed during the acute infection, is associated with an elevated IL-21+ CD4 T subset and these cells bear a phenotypic resemblance to T follicular helper cells. We observed that, during per-oral microsporidial infection, IL-21 was critical for the generation of an optimal effector CD8 T cell immunity. Sharply decreased effector KLRG1+ CD8 response was observed in IL-21R knockout mice and while these cells exhibited reduced functional properties they retained the ability to proliferate. The role of IL-21 in the generation of CD8 effectors was cell intrinsic, as stronger defects were observed in the IL-21 deficient compartment from the bone marrow chimeric mice (IL-21R KO/wild type). These findings are different from those reported for viral infections where IL-21 has been primarily associated with the generation and maintenance of CD8 memory response. To the best of our knowledge, this report demonstrates a critical role for IL-21 in the generation of a primary effector CD8 T cells response to an infectious disease model.

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Interleukin-21 Is a Critical Regulator of CD4 and CD8 T Cell Survival during Priming under Interleukin-2 Deprivation Conditions

Cited by 15 publications

References 56 publications

Effector CD8 T cell immunity in microsporidial infection: a lone defense mechanism

Effector CD8 T cell immunity in microsporidial infection: a lone defense mechanism

Immune Activation Is Associated with CD8 T Cell Interleukin-21 Production in HIV-1-Infected Individuals

IL-21 Is Important for Induction of KLRG1+ Effector CD8 T Cells during Acute Intracellular Infection

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