Role of IL-7 as a Key Immune Response Primer

National Institute Of Allergy And Infectious Diseases

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Abstract

Interleukin-7 (IL-7) is the principal T-cell homeostatic factor in the body and is critical to reconstitute the normal T-lymphocyte pool when lymphopenia (loss of lymphocytes) occurs, as it happens in the course of infectious diseases (for example HIV/AIDS) or as a consequence of medical interventions (for example chemotherapy for cancer treatment). We recently discovered a new function of this cytokine, which may not only be critical for preparing the body to face the infectious complications of lymphopenia, but also to mount effective immune responses against other diseases, including cancer. During this year, we found that, at suprahomeostatic concentrations that are typical of lymphopenia, IL-7 is a potent inducer of selected pro-inflammatory chemokines and cytokines that are involved in antimicrobial defense and, in general, in mounting robust immune responses. However, IL-7 stops short of inducing a full-blown inflammatory reaction, which may have detrimental side effects, as it does not induce the production of IFN-gamma and IL-2. Notably, this effect of IL-7 occurs in the absence of any other concomitant stimulation, but it requires an active and contact-dependent cross-talk between T cells and monocytes. An in-depth characterization of the mechanisms that mediate this effect of IL-7 has documented a key role of another cytokine, TNF-alpha, which is potently induced by IL-7. We have also characterized the signal transduction pathways that mediate the IL-7 effects and the gene expression profiles by RNAseq analysis, both of which has unraveled a complex program of intracellular signaling and gene expression induced by IL-7 and aimed at establishing a state of preparedness against infectious diseases that may affect patients with lymphopenia. This concept was corroborated by experiments with Toll-like receptor (TLR) activators, stimulants that mimic the effects of microbial pathogens, which showed that priming with IL-7 dramatically enhances the response to multiple TLR activators, resulting in the production of high levels of interferon-gamma, a pivotal antimicrobial cytokine, as well as a dramatic enhancement of other cytokines and chemokines. Although the primary purpose of this IL-7-mediated program seems to be antimicrobial defense in patients with lymphopenia, it is clear that it might also apply to other disease conditions in which IL-7 levels are increased (e.g., autoimmune diseases), and might be medically exploited to amplify immune responses against infections and cancer, as well as in the setting of vaccination. Strikingly, we also found that interferon-alpha acts as a potent antagonist of IL-7, abrogating its priming effects on antimicrobial and pro-inflammatory responses. We are currently trying to dissect the fine molecular mechanisms of this antagonistic effect of IFN-alpha, which may be exploited therapeutically to overcome immunosuppression or, conversely, to reduce unwanted or dysregulated immune responses. Overall, our results demonstrate that IL-7 initiates a program of immunologic amplification, primarily directed at promoting the host defenses against invading microbes, through the concerted recruitment of multiple cytokines and chemokines, and the activation of a cascade of genes that prepare the immune system for potent immune responses. These results illustrate a novel mechanism of antimicrobial control that does not require triggering of a full T-cell activation program, which may have unwanted inflammatory effects, and that the body can implement under conditions of lymphopenia in an attempt to reconstitute the lost immune function.