Physiological microbial exposure transiently inhibits mouse lung ILC2 responses to allergens.

Lung group 2 innate lymphoid cells (ILC2s) control the nature of immune responses to airway allergens. Some microbial products, including those that stimulate interferons, block ILC2 activation, but whether this occurs after natural infections or causes durable ILC2 inhibition is unclear. In the present study, we cohoused laboratory and pet store mice as a model of physiological microbial exposure. Laboratory mice cohoused for 2 weeks had impaired ILC2 responses and reduced lung eosinophilia to intranasal allergens, whereas these responses were restored in mice cohoused for ≥2 months. ILC2 inhibition at 2 weeks correlated with increased interferon receptor signaling, which waned by 2 months of cohousing. Reinduction of interferons in 2-month cohoused mice blocked ILC2 activation. These findings suggest that ILC2s respond dynamically to environmental cues and that microbial exposures do not control long-term desensitization of innate type 2 responses to allergens.

The Functional Requirement for CD69 in Establishment of Resident Memory CD8+ T Cells Varies with Tissue Location.

Recent studies have characterized populations of memory CD8+ T cells that do not recirculate through the blood but are, instead, retained in nonlymphoid tissues. Such CD8+ tissue resident memory T cells (TRM) are critical for pathogen control at barrier sites. Identifying TRM and defining the basis for their tissue residency is therefore of considerable importance for understanding protective immunity and improved vaccine design. Expression of the molecule CD69 is widely used as a definitive marker for TRM, yet it is unclear whether CD69 is universally required for producing or retaining TRM Using multiple mouse models of acute immunization, we found that the functional requirement for CD69 was highly variable, depending on the tissue examined, playing no detectable role in generation of TRM at some sites (such as the small intestine), whereas CD69 was critical for establishing resident cells in the kidney. Likewise, forced expression of CD69 (but not expression of a CD69 mutant unable to bind the egress factor S1PR1) promoted CD8+ TRM generation in the kidney but not in other tissues. Our findings indicate that the functional relevance of CD69 in generation and maintenance of CD8+ TRM varies considerably, chiefly dependent on the specific nonlymphoid tissue studied. Together with previous reports that suggest uncoupling of CD69 expression and tissue residency, these findings prompt caution in reliance on CD69 expression as a consistent marker of CD8+ TRM.

The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells.

Extracellular ATP (eATP) is an ancient 'danger signal' used by eukaryotes to detect cellular damage1. In mice and humans, the release of eATP during inflammation or injury stimulates both innate immune activation and chronic pain through the purinergic receptor P2RX72-4. It is unclear, however, whether this pathway influences the generation of immunological memory, a hallmark of the adaptive immune system that constitutes the basis of vaccines and protective immunity against re-infection5,6. Here we show that P2RX7 is required for the establishment, maintenance and functionality of long-lived central and tissue-resident memory CD8+ T cell populations in mice. By contrast, P2RX7 is not required for the generation of short-lived effector CD8+ T cells. Mechanistically, P2RX7 promotes mitochondrial homeostasis and metabolic function in differentiating memory CD8+ T cells, at least in part by inducing AMP-activated protein kinase. Pharmacological inhibitors of P2RX7 provoked dysregulated metabolism and differentiation of activated mouse and human CD8+ T cells in vitro, and transient P2RX7 blockade in vivo ameliorated neuropathic pain but also compromised production of CD8+ memory T cells. These findings show that activation of P2RX7 by eATP provides a common currency that both alerts the nervous and immune system to tissue damage, and promotes the metabolic fitness and survival of the most durable and functionally relevant memory CD8+ T cell populations.