Age-dependent rise in IFN-γ competence undermines effective type 2 responses to nematode infection

The efficient induction of type 2 immune responses is central to the control of helminth infections. Previous studies demonstrated that strong Th1 responses driven by intracellular pathogens as well as a bias for type 1 activity in senescent mice impedes the generation of Th2 responses and the control of intestinal nematode infections. Here, we show that the spontaneous differentiation of Th1 cells and their expansion with age restrains type 2 immunity to infection with the small intestinal nematode H. polygyrus much earlier in life than previously anticipated. This includes the more extensive induction of IFN-γ competent, nematode-specific Th2/1 hybrid cells in BALB/c mice older than three months compared to younger animals. In C57BL/6 mice, Th1 cells accumulate more rapidly at steady state, translating to elevated Th2/1 differentiation and poor control of parasite fitness in primary infections experienced at a young age. Blocking of early IFN-γ and IL-12 signals during the first week of nematode infection leads to sharply decreased Th2/1 differentiation and promotes resistance in both mouse lines. Together, these data suggest that IFN-γ competent, type 1 like effector cells spontaneously accumulating in the vertebrate host progressively curtail the effectiveness of anti-nematode type 2 responses with rising host age

Rolle von IFN-γ bei der Immunität und Kontrolle gastrointestinaler Nematodeninfektionen

Infections by gastrointestinal nematodes mandate an effective type 2 response for the parasite clearance. In line with the cross-regulatory nature of Th1 lineage specifying factors on the differentiation of Th2 cells seen at the molecular level, strong type 1 activity resulted by inflammation associated with senescence, specific genetic predisposition and co-infections with intracellular pathogens exacerbate the Th2 responses resulting in poor resistance in nematode infections. Despite reported cross-regulation, the Th1 and Th2 pathways are not mutually exclusive as polarization with IFN-g, IL-12 and IL-4 results in the generation of T-bet and GATA-3 co-expressing Th2/1 cells in vitro. Th2/1 cells are also induced naturally in nematode infections (Affinass et al., 2018; Bock et al., 2017; Peine et al., 2013). In the current study we demonstrate that the IFN-g competence progressively rises with the age of uninfected BALB/c mice displaying high resistance to nematode infection. The elevated type 1 bias in 5-10 months old compared to 2-3 months old mice resulted in poor parasite control manifested by higher female fecundity in the mature cohort infected with H. polygyrus. The poor resistance was accompanied by stronger generation and mucosal accumulation of Th2/1 hybrid cells and elevated proportions of parasite specific IFN-g producing cells. Substantiating the above findings, restriction of IFN-g availability in the priming phase of nematode infection led to improved resistance coinciding with sharp reduction in systemic and mucosal Th2/1 cells and a near complete absence of parasite specific IFN-g producing cells. Conversely, supplementation of early IFN-g availability led to impaired parasite control associated with robust expansion of Th2/1 cells and a significant rise in IFN-g producing cells in parasite specific T cell pool. Importantly, elevated IFN-g availability did not inhibit classical Th2 cells in the long run and rather promoted an accumulation of systemic GATA-3+ Teff cells in IFN-g treated BALB/c mice. The increased parasite egg production upon IFN-g treatment was traced back to the increased fitness of the L4 larvae maturating in the gut of IFN-g treated mice. In line with the findings in differently aged mice, C57BL/6 mice genetically predisposed to higher susceptibility in H. polygyrus infection more rapidly accumulate Th1 cells at steady state compared to resistant BALB/c mice. The elevated type 1 activity in C57BL/6 mice translated to greater accumulation of small intestinal Th2/1 cells post infection and poor resistance compared to BALB/c mice. However, the stark differences seen between the strains at younger age leveled out in older mice due to increased IFN-g competence and increased bias in favor of Th2/1 cells in mature BALB/c mice. Restricting IFN-g availability in C57BL/6 mice led to increased resistance thereby substantiating the significance of IFN-g in differential susceptibility across inbred lines. Overall, our findings report an age-dependent reduction in anti-nematode type 2 immunity resulted by steady state accumulation of IFN-g competent effector cells in the vertebrate host.Infektionen durch Magen-Darm-Nematoden erfordern eine effektive Typ-2 Immunantwort für die Beseitigung des Parasiten. Entsprechend der Kreuzregulation der THelferzelldifferenzierung durch molekulare Faktoren, welche die Th1-Differenzierung unterstützen, kann eine starke Typ-1-Immunaktivität als Ergebnis von Immunseneszenz, spezifischer genetischer Prädisposition oder der Ko-Infektionen mit intrazellulären Pathogenen die Ausbildung von Th2-Antworten behindern, was zu einer geringen Resistenz gegen Nematodeninfektionen führen kann. Vorherige in vitro und in vivo Studien haben gezeigt, dass sich die Differenzierungswege in Th2- beziehungsweise Th1- Zellen nicht gegenseitig ausschließen, da T-Helferzellen unter gleichzeitiger Einwirkung der Th1-beziehungsweise Th2-polarisierenden Zytokine IFN-g/IL-12 und IL-4 einen Th2/1-Hybridphänotyp annehmen. Dieser Differenzierungsstatus ist durch die Koexpression von GATA-3 und T-bet gekennzeichnet und vorherige Arbeiten haben gezeigt, dass die Differenzierung von Th2/1-Hybridzellen auch als natürliche Reaktion auf Infektionen mit Darmnematoden vorkommt (Affinass et al., 2018; Bock et al., 2017; Peine et al., 2013). Die vorliegende Arbeit zeigt, dass es in gesunden Labormäusen der gegen Nematodeninfektionen hoch resistenten BALB/c-Linie mit steigendem Alter zu einer Zunahme der IFN-g-Kompetenz kommt. Als Konsequenz dieses Th1-Bias ist die Kontrolle einer Nematodeninfektionen beeinträchtigt, wenn BALB/c-Mäuse im Alter von 5-10 Monaten anstatt von 2-3 Monaten mit H. polygyrus infiziert werden, was aus der erhöhten Eiproduktion der Würmer in älteren Mäusen ersichtlich wird. Die verminderte Resistenz der geht einher mit der Anreicherung von Th2/1-Hybridzellen in der Mukosa und mit einem erhöhten Anteil von IFN-g produzierenden, parasiten-spezifischen T-Helferzellen. Dieser Zusammenhang konnte durch die Blockade von IFN-g in der frühen Phase der Immunantwort weiter belegt werden. Dieser Ansatz führte zu einer drastischen Reduktion von systemischen und mukosalen Th2/1-Hybridantworten und dem nahezu vollständigen Ausbleiben der IFN-g Produktion durch parasiten-spezifische T-Zellen, wodurch die Resistenz erhöhte wurde. Wurde jedoch die Verfügbarkeit von IFN-g in der frühen Infektionsphase durch Gabe des Zytokins erhöht, so resultierte dies in der starken Expansion von Th2/1 Hybridzellen, einer signifikanten Zunahme von IFN-g produzierenden Zellen in der parasiten-spezifischen T-Zellpopulation und der verminderten Kontrolle der Parasiteninfektion. Zudem zeigte sich, dass die erhöhte Verfügbarkeit von IFN-g die Differenzierung von klassischen GATA-3+ Th2-Zellen langfristig nicht inhibiert, sondern dass es nach IFN-g-Behandlung von BALB/c Mäusen zu einer gesteigerten systemischen Akkumulation von GATA-3+ Zellen kommt. Weiter konnte die nach IFN-g Gabe erhöhte Eiproduktion durch die Parasiten mit einer erhöhten Fitness des sich im Darm entwickelnden vierten Larvenstadiums nach IFN-g Gabe in Zusammenhang gebracht werden. Abweichend von der verzögerten, altersbedingten Zunahme der IFN-g-Kompetenz von BALB/c Mäusen zeigten Mäuse der C57BL/6-Linie mit einer genetisch veranlagten hohen Empfänglichkeit für die H. polygyrus-Infektion bereits als junge Tiere eine Anreicherung von Th1-Zellen in Abwesenheit von Infektionen. Nach Wurminfektion resultierte die stärkere Typ-1 Aktivität der C57BL/6 Linie in der stärkeren Anreicherung von Th2/1-Zellen im infizierten Dünndarm und in der geringeren Resistenz im Vergleich zur BALB/c Linie. Diese deutlichen Unterschiede zwischen den beiden Mauslinien zeigten sich insbesondere bei jungen Tieren. In älteren Tieren glichen sich jedoch die Reaktionen auf die Infektion durch die Zunahme der IFN-g Kompetenz und die verstärkte Bildung von Th2/1 Zellen in älteren BALB/c Mäusen an. Die Beschränkung der IFN-g Verfügbarkeit in C57BL/6 Mäusen führte zu einer erhöhten Resistenz, was die Bedeutung von IFN-g für die unterschiedliche Empfänglichkeit von Mauslinien unterstreicht. Zusammenfassend zeigt diese Studie also eine altersabhängige Abnahme der Typ-2 abhängigen Immunität gegenüber Nematodeninfektionen durch die spontane Zunahme von IFN-g kompetenten Zellen

Immune aging: biological mechanisms, clinical symptoms, and management in lung transplant recipients

While chronologic age can be precisely defined, clinical manifestations of advanced age occur in different ways and at different rates across individuals. The observed phenotype of advanced age likely reflects a superposition of several biological aging mechanisms which have gained increasing attention as the world contends with an aging population. Even within the immune system, there are multiple age-associated biological mechanisms at play, including telomere dysfunction, epigenetic dysregulation, immune senescence programs, and mitochondrial dysfunction. These biological mechanisms have associated clinical syndromes, such as telomere dysfunction leading to short telomere syndrome (STS), and optimal patient management may require recognition of biologically based aging syndromes. Within the clinical context of lung transplantation, select immune aging mechanisms are particularly pronounced. Indeed, STS is increasingly recognized as an indication for lung transplantation. At the same time, common aging phenotypes may be evoked by the stress of transplantation because lung allografts face a potent immune response, necessitating higher levels of immune suppression and associated toxicities, relative to other solid organs. Age-associated conditions exacerbated by lung transplant include bone marrow suppression, herpes viral infections, liver cirrhosis, hypogammaglobulinemia, frailty, and cancer risk. This review aims to dissect the molecular mechanisms of immune aging and describe their clinical manifestations in the context of lung transplantation. While these mechanisms are more likely to manifest in the context of lung transplantation, this mechanism-based approach to clinical syndromes of immune aging has broad relevance to geriatric medicine

Short Airway Telomeres are Associated with Primary Graft Dysfunction and Chronic Lung Allograft Dysfunction

Primary graft dysfunction (PGD) is a major risk factor for chronic lung allograft dysfunction (CLAD) following lung transplantation, but the mechanisms linking these pathologies are poorly understood. We hypothesized that the replicative stress induced by PGD would lead to erosion of telomeres, and that this telomere dysfunction could potentiate CLAD. In a longitudinal cohort of 72 lung transplant recipients with >6 years median follow-up time, we assessed tissue telomere length, PGD grade, and freedom from CLAD. Epithelial telomere length and fibrosis-associated gene expression were assessed on endobronchial biopsies taken at 2 - 4 weeks post-transplant by TeloFISH assay and nanoString digital RNA counting. Negative-binomial mixed-effects and Cox-proportional hazards models accounted for TeloFISH staining batch effects and subject characteristics including donor age. Increasing grade of PGD severity was associated with shorter airway epithelial telomere lengths (P = 0.01). Transcriptomic analysis of fibrosis-associated genes showed alteration in fibrotic pathways in airway tissue recovering from PGD, while telomere dysfunction was associated with inflammation and impaired remodeling. Shorter tissue telomere length was in turn associated with increased CLAD risk, with a hazard ratio of 1.89 (95% CI 1.16 - 3.06) per standard deviation decrease in airway telomere length, after adjusting for subject characteristics. PGD may accelerate telomere dysfunction, potentiating immune responses and dysregulated repair. Epithelial cell telomere dysfunction may represent one of several mechanisms linking PGD to CLAD