IL-21 Is Required to Control Chronic Viral Infection

Abstract

CD4 + and CD8 + T cell functions are rapidly aborted during chronic infection, preventing viral clearance. CD4 + T cell help is required throughout chronic infection so as to sustain CD8 + T cell responses; however, the necessary factor(s) provided by CD4 + T cells are currently unknown. Using a mouse model of chronic viral infection, we demonstrated that interleukin-21 (IL-21) is an essential component of CD4 + T cell help. In the absence of IL-21 signaling, despite elevated CD4 + T cell responses, CD8 + T cell responses are severely impaired. CD8 + T cells directly require IL-21 to avoid deletion, maintain immunity, and resolve persistent infection. Thus, IL-21 specifically sustains CD8 + T cell effector activity and provides a mechanism of CD4 + T cell help during chronic viral infection.During chronic viral infections, antiviral CD4 + and CD8 + T cells become non-responsive to viral antigens and are either physically deleted or persist in a nonfunctional "exhausted" state, unable to produce important antiviral and immunostimulatory cytokines such as interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ); lyse virally infected cells; or proliferate (1-4). To date, the majority of work analyzing T cell exhaustion during chronic viral infection has focused on CD8 + T cells; however, CD4 + T cells also exhibit reduced function, thus further exacerbating viral persistence. CD4 + T cells are required throughout chronic viral infection in order to sustain CD8 + T cell function and control infection, prevent deletion of high-affinity antiviral CD8 + T cells, and eventually resolve the infection (5-7). The loss of CD4 + and CD8 + T cell function is associated with viruses that establish chronic viral infections in their hosts: HIV and hepatitis B and hepatitis C virus (HCV) in humans and lymphocytic chorio-meningitis virus (LCMV) in rodents (8)(9)(10)(11)(12). Chronic LCMV infection is eventually controlled in the periphery 60 to 80 days after infection in a CD4 + T cell-dependent manner, suggesting that exhausted CD4 + T cells retain helper activity. Expression of the key CD4 + T cell helper cytokine IL-2, however, is rapidly extinguished during viral persistence (4,13), indicating that an alternative helper mechanism is being implemented.To determine how CD4 + T cells help CD8 + T cells to clear a viral infection, we infected mice with the Armstrong strain of LCMV (Arm) that induces a robust T cell response, resulting in viral clearance within 8 to 10 days or with the Clone 13 strain of LCMV (Cl 13) that generates a chronic infection due to the up-regulation of immunosuppressive factors that induce a dramatic depletion and inactivation of virus-specific T cells (14-18). LCMV-Arm and -Cl 13 share identical CD4 + and CD8 + T cell epitopes, enabling direct comparison of

Dendritic Cell Inhibition Is Connected to Exhaustion of CD8+ T Cell Polyfunctionality during Chronic Hepatitis C Virus Infection

“…1, Supplemental Table 1). Although the requirement for CD4 + T cell help throughout chronic infection to sustain CD8 + T cell function (37,38) is not in dispute, PRRactivated DCs could represent a backup mechanism for situations in which CD4 responses are defective. This would be in keeping with findings by other investigators in which the adoptive transfer of autologous DCs loaded in vitro with whole-inactivated HIV-1 or therapeutic vaccination with a recombinant viral vector, both of which recruit functional DCs into the APC pool, induces protective antiviral immunity and viral suppression in the setting of chronic HIV-1 infection (39) and synergizes with PD-L1 neutralization to clear infection in CD4 + T cell help-deficient LCMV clone 13-infected mice (40), respectively.…”

Antigen-Independent Induction of Tim-3 Expression on Human T Cells by the Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Is Associated with Proliferation and Is Dependent on the Phosphoinositide 3-Kinase Pathway

“…The common gc cytokines, including IL-7, IL-15, and IL-21, were reported to be above normal levels in chronic HIV-1 infection (19)(20)(21)(22)(23) and, thus, were potential candidates behind Tim-3 induction on T cells. To further understand Tim-3 upregulation in the context of immune responses, PBMCs from healthy donors were stimulated with various cytokines, including members of the common gc family, and Tim-3 expression was analyzed on CD4 + and CD8 + T cells following a 6-d period of stimulation compared with cells cultured in plain medium alone (CD4 + , 5.6 6 2.9%; CD8 + , 6.1 6 5.1%) ( Fig.…”

“…Lastly, we hypothesized that some other soluble inflammatory factor could be behind the Tim-3 expression witnessed during immune activation and tested the common g-chain (gc) cytokines on T cells from individuals not infected with HIV-1. Indeed, IL-7, IL-15, and IL-21 were reported to be elevated in blood plasma during the course of chronic infections (19)(20)(21)(22)(23) and, thus, are likely candidates behind global Tim-3 upregulation.…”

Diagnostic Value of Interleukin 21 and Carcinoembryonic Antigen Levels in Malignant Pleural Effusions

“…Care was taken to make sure that the patients matched the diagnostic criterias and didn't suffer from chronic diseases such as chronic viral infections (Elsaesser et al, 2009), SLE (Sarra et al, 2010), Rheumatoid Arthritis (Daha et al, 2009), Psoriasis (Liu et al, 2008) and Inflammatory bowel diseases (Liu et al, 2009). Written consent was obtained from all the patients concerned in order to perform this study.…”