Giacomin, P. R. | Search bioRxiv

bioRxiv2024

Lung epithelial progenitor-mediated release of TGF-β regulates induction and persistence of lung CD8+ TRM cells following mucosal BCG vaccination

A principal reason for the high global morbidity and mortality of tuberculosis (TB) is the lack of efficacy of the only licensed TB vaccine, Bacillus Calmette-Guerin (BCG), as parenteral BCG does not induce local pulmonary immune memory. Animal studies have shown that mucosal BCG vaccination provides superior protection against TB due to generation of lung resident memory T cells (TRM). Here, we demonstrated that following mucosal vaccination with the genetically modified virulent BCG strain, BCG::RD1, distal airway epithelial progenitors were mobilized to assist with restoration of alveolar epithelium. By way of their migration-mediated activation of latent TGF-{beta}, lung CD8+ TRM differentiation was induced. Mucosal vaccinations using nonvirulent strains of BCG in which airway epithelial progenitors were not mobilized, as well as genetic inhibition of migration-mediated activation of TGF-{beta}, resulted in significantly lower numbers of lung CD8+ TRM. In addition, we discovered CD8+ cells with ex-lung and stem-like TRM phenotypes that persisted in the lung-draining mediastinal lymph nodes for up to four months following mucosal BCG vaccination. These results link airway epithelial progenitor-mediated repair of injured lung tissue with induction of resident T cell memory and delineate why persistence of TRM in the lung is short-lived. These findings may explain why mucosal vaccination with virulent BCG strains is more protective against TB and thus have notable implications for future TB vaccine development. One Sentence SummaryFollowing lung damage due to inhalation of virulent BCG, distal airway epithelial progenitor cells interact with lung CD8+ T cells to induce their differentiation into resident memory T cells via migration-mediated activation of TGF-{beta}.

immunology↗

bioRxiv2019

Treatment of mice with IL2-complex enhances inflammasome-driven IFN-γ production and prevents lethal toxoplasmosis

Toxoplasmic encephalitis is an AIDS-defining condition in HIV+ individuals. The decline of IFN-{gamma}-producing CD4+ T cells in AIDS is a major contributing factor in reactivation of quiescent Toxoplasma gondii to an actively replicating stage of infection. Hence, it is important to identify CD4-independent mechanisms to control acute T. gondii infection. Here we have investigated the targeted expansion and regulation of IFN-{gamma} production by CD8+ T cells, DN T cells and NK cells in response to T. gondii infection using IL-2 complex (IL2C) pre-treatment in an acute in vivo mouse model. Our results show that expansion of CD8+ T cells, DN T cells and NK cell by S4B6 IL2C treatment increases survival rates of mice infected with T. gondii and this increased survival is dependent on both IL-12- and IL-18-driven IFN-{gamma} production. Processing and secretion of IFN-{gamma}-inducing, bioactive IL-18 is dependent on the sensing of active parasite invasion by multiple redundant inflammasome sensors in multiple hematopoietic cell types but independent from T. gondii-derived dense granule (GRA) proteins. Our results provide evidence for a protective role of IL2C-mediated expansion of CD8+ T cells, DN T cells and NK cells in murine toxoplasmosis and may represent a promising adjunct therapy for acute toxoplasmosis.\n\nAuthor SummaryA third of the worlds population is chronically infected with the parasite Toxoplasma gondii. In most cases the infection is asymptomatic, but in individuals suffering from AIDS, reactivation of brain and muscle cysts containing T. gondii is a significant cause of death. The gradual decline of CD4 T cells, the hallmark of AIDS, is believed to be a major contributing factor in reactivation of T. gondii infection and the development of acute disease. In this study, we show that targeted expansion of non-CD4 immune cell subsets can prevent severe disease and premature death via increased availability of interferon gamma-producing immune cells. We also demonstrate that the upstream signaling molecule interleukin-18 is required for the protective immune response by non-CD4 cells and show that the sensing of active parasite invasion by danger recognition molecules is crucial. Our findings reveal that targeted cell expansion may be a promising therapy in toxoplasmosis and suggests that the development of novel intervention strategies targeting danger recognition pathways may be useful against toxoplasmosis, particularly in the context of AIDS.

microbiology↗