IL-7 Engages Multiple Mechanisms to Overcome Chronic Viral Infection and Limit Organ Pathology

Abstract

Understanding the factors that impede immune responses to persistent viruses is essential in designing therapies for HIV infection. Mice infected with LCMV clone-13 have persistent high-level viremia and a dysfunctional immune response. Interleukin-7, a cytokine that is critical for immune development and homeostasis, was used here to promote immunity toward clone-13, enabling elucidation of the inhibitory pathways underlying impaired antiviral immune response. Mechanistically, IL-7 downregulated a critical repressor of cytokine signaling, Socs3, resulting in amplified cytokine production, increased T cell effector function and numbers, and viral clearance. IL-7 enhanced thymic output to expand the naive T cell pool, including T cells that were not LCMV specific. Additionally, IL-7 promoted production of cytoprotective IL-22 that abrogated liver pathology. The IL-7-mediated effects were dependent on endogenous IL-6. These attributes of IL-7 have profound implications for its use as a therapeutic in the treatment of chronic viral diseases.

IL-7 Licenses Activation of Human Liver Intrasinusoidal Mucosal-Associated Invariant T Cells

“…Thus, the functional link between IL-7 and MAIT cells suggests a scenario in which MAIT cells might be fully activated only in the presence of the ongoing innate responses of other intrahepatic cells (e.g., Kupffer or dendritic cells) that induce IL-7 production by hepatocytes. Mechanistically, IL-7 licenses MAIT cells by decreasing SOCS3 expression, as previously found with other T cell populations in mice (30), and by upregulating the expression of the TCR complex and other molecules involved in TCR triggering. In addition, IL-7 boosted the production of IL-17A by MAIT cells upon anti-CD3/CD28-mediated TCR activation, providing evidence that TCR stimulation, in addition to mitogen stimulation (16,17), can induce the release of this cytokine.…”

“…For example, IL-1b increases the cell response to anti-CD3 stimulation and encourages maturation toward IL-17A production in CD161 + T cells (25). Similarly, conventional CD4 + T cells with a Th17 signature possess extended functional plasticity, and IL-7 (29,30) or a combination of IL-1b and IL-23 (31,32) may reduce the T cell-activation threshold and positively influence differentiation toward Th17 cells. Because Liv-MAIT cells produced high quantities of IL-17A only after mitogen stimulation, we tested whether inflammatory cytokines influence the maturation and responsiveness of Liv-MAIT cells to TCR-mediated stimulation.…”

“…Emphasis was placed on testing the effect of IL-7 for three reasons: MAIT cells express high levels of IL-7R (Fig. 2B); hepatocytes are the primary source of inducible IL-7 during inflammatory processes in the liver (33); and IL-7 is capable of modulating IL-17A production in memory CCR6 + CD4 + T cells and in gd T cells (34), as well as increasing T cell responsiveness (30).…”

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

“…Of note, however, was the fact that the absolute number of PD-1 + T cells increased markedly during IL-7 treatment in LCMV-infected mice (see figure 3B in Ref. 52), which then decreased at the end of IL-7 therapy, at which point the virus was also undetectable. Furthermore, in both of these studies, PD-1 was primarily measured after viral and Ag clearance and not during IL-7 administration.…”

IL-2 and IL-7 Determine the Homeostatic Balance between the Regulatory and Conventional CD4+ T Cell Compartments during Peripheral T Cell Reconstitution

“…Conversely, administration of IL-7 in humans induces expansion of naive and memory T cell subsets (49)(50)(51) and, in some clinical trials, a relative decrease in the percentage of regulatory CD4 + T cells was observed (52). Thus, on one hand, the capacity of IL-7 to augment conventional T cell proliferation with minimal concomitant regulatory T cell expansion may be clinically exploitable in the treatment of patients with lymphopenia, especially in the case of chronic viral diseases (53) or cancer immunotherapy (54). On the other hand, increased systemic IL-7 levels during lymphopenia may lead to an imbalance between the conventional and regulatory T cell compartments at the expense of regulatory T cells and may exacerbate deleterious immune reactions, such as graft-versus-host disease (55) or autoimmunity (56)(57)(58).…”