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Principal Investigator: paolo lusso
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2024
Award: $705,216
Funding agency: National Institute of Allergy and Infectious Diseases
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 COVID-19) or as a consequence of medical interventions (for example chemotherapy for cancer treatment). Our previous work demonstrated that IL-7 is a potent inducer of the main gut-homing integrin, alpha4beta7 (a4b7), and thereby redirects nave T cells to the intestine, which is a primary anatomical site for HIV-1 replication. Furthermore, we found that a4b7 is incorporated into the HIV-1 virion during its egress from infected cells. More recently, we collaborated in the demonstration that another host receptor, P-selectin glycoprotein ligand-1 (PSGL-1/CD162), is incorporated into HIV-1 virions both in vitro and in vivo.
With regard to IL-7, we have recently discovered a new function of this cytokine, which may be critical for preparing the body to face the most severe complications of lymphopenia. We found that, at suprahomeostatic concentrations that are typical of lymphopenia, IL-7 is a potent inducer of anti-HIV chemokines (i.e., RANTES/CCL5, MIP-1a/CCL3 and MIP-1b/CCL4) and other chemokines and cytokines that are involved in antimicrobial immune responses. This effect 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 TNF-alpha. We have also characterized the signal transduction that mediates the IL-7 effects and performed 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 of resting human peripheral blood cells with IL-7 dramatically enhanced the response to multiple TLR activators, resulting in the production of high levels of interferon-gamma (IFN-g) a key antimicrobial cytokine. We have also re-evaluated the microarray results from a study of in vivo IL-7 treatment that we had performed in macaques 10 years ago (Vassena et al., PLoS Path 2012) and found that many of the genes activated in vitro by IL-7 are also induced in vivo in the macaque model. Finally, we have started to study the effect of interferon-alpha as a potential antagonist of the IL-7 effects. Overall, our results demonstrate that IL-7 initiates a program of immunologic defense 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 antimicrobial responses. These results illustrate a novel potential mechanism of antimicrobial control that does not require the 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 and facilitate non-cytolytic immune-mediated suppression of HIV-1.
Terms: <(IFN) α><(IFN)-α><(IFN)α><(TNF)-α><ACT2><AIDS Virus><AIDS/HIV><AT744.1><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Act-2><Affect><Alferon><Anatomic Sites><Anatomic structures><Anatomy><Autoregulation><Blood Cells><Blood monocyte><CCL3><CCL3 gene><CCL4><CCL4 gene><CCL5><CD162 antigen><COVID-19><CV-19><Cachectin><Cancer Treatment><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Immune Function><Chemokine (C-C Motif) Ligand 4><Chemokine (C-C Motif) Ligand 5><Chemokine (C-C motif) Ligand 3><Chemokine, CC Motif, Ligand 4><Chemotactic Cytokines><Chemotherapy Protocol><Chemotherapy Regimen><Chemotherapy-Oncologic Procedure><Collaborations><Combination Chemotherapy Regimen><Communicable Diseases><Complex><Coronavirus Infectious Disease 2019><D17S136E><Disease><Disorder><Face><G0S19-1><Gene Expression><Genes><HIV><HIV-1><HIV-I><HIV/AIDS><HIV1><Homeostasis><Homing><Homologous Chemotactic Cytokines><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><IFN Alpha><IFN α><IFN-Gamma><IFN-g><IFN-α><IFN-γ><IFNG><IFNa><IFNα><IFNγ><IL-7><IL-7 Gene><IL7><IL7 Protein><IL7 gene><IMiD><Immune><Immune Activation 2><Immune Interferon><Immune modulatory therapeutic><Immune response><Immune system><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunomodulation><In Vitro><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammatory><Integrins><Integrins Extracellular Matrix><Intercrines><Interferon Alfa-n3><Interferon Gamma><Interferon Type II><Interferon alpha><Interferon-α><Interleukin 7 Precursor><Interleukin 7 Precursor Gene><Interleukin-7><Interleukin-7 Gene><Intervention><Intervention Strategies><Intestinal><Intestines><Intracellular Communication and Signaling><Invaded><Knowledge><LAV-HTLV-III><LD78ALPHA><Laboratories><Leukocyte Interferon><Lymphadenopathy-Associated Virus><Lymphatic cell><Lymphoblast Interferon><Lymphoblastoid Interferon><Lymphocyte><Lymphocytic><Lymphocytopenia><Lymphopenia><Lymphopoietin-1><MGC17164><MIP 1alpha><MIP-1-alpha><MIP-1a><MIP1A><MIP1B><MIP1B1><Macaca><Macaque><Macrophage Inflammatory Protein 1-Beta><Macrophage-Derived TNF><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Marrow monocyte><Mediating><Medical><Microbe><Modeling><Modern Man><Monocyte-Derived TNF><P-selectin glycoprotein ligand-1><P-selectin ligand protein><PSGL-1><Pathogenesis><Patients><Peripheral Blood Cell><Physiologic><Physiological><Physiological Homeostasis><Preparedness><Prevention><Production><Quimioterapia><RANTES><RNA Seq><RNA sequencing><RNAseq><Readiness><Receptor Protein><Research><Rest><Role><SCYA3><SCYA4><SCYA5><SIS cytokines><SIS delta><SIS-delta><SISd><Signal Transduction><Signal Transduction Systems><Signaling><Small Inducible Cytokine A3><Small Inducible Cytokine A4><Small Inducible Cytokine A5><Stem Cell Inhibitor><Stimulant><T-Cell Activation><T-Cell RANTES Protein><T-Cell Specific Protein p288><T-Cells><T-Lymphocyte><TCP228><TLR protein><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Toll-Like Receptor Family Gene><Toll-like receptors><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Virion><Virus Particle><Virus-HIV><Work><activate T cells><antagonism><antagonist><anti-cancer therapy><anti-microbial><antimicrobial><biological signal transduction><bowel><cancer chemotherapy><cancer therapy><cancer-directed therapy><chemoattractant cytokine><chemokine><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cytokine><experiment><experimental research><experimental study><experiments><faces><facial><host response><immune function><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulation><immune modulatory agents><immune modulatory drugs><immune regulation><immune system response><immunologic reactivity control><immunomodulating agents><immunomodulating drugs><immunomodulator agent><immunomodulator drug><immunomodulator medication><immunomodulator prodrug><immunomodulator therapeutic><immunomodulatory><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><immunoregulation><immunoregulatory><immunoresponse><in vivo><interest><interventional strategy><lFN-Gamma><lymph cell><microbe pathogen><microbial pathogen><microorganism><monocyte><novel><pathogen><pathogenic microbe><programs><receptor><reconstitute><reconstitution><recruit><response><social role><thymus derived lymphocyte><transcriptome sequencing><transcriptomic sequencing>