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Key Points Memory T cells are established at both lymphoid and peripheral sites following the clearance of an invading pathogen. However, memory T-cell transfer and parabiosis studies have shown that the migration of circulating memory T cells into some peripheral tissues, such as the skin, gut, lung airways and brain, is highly restricted. The ability of memory T cells to selectively migrate into different peripheral tissues is controlled by the expression of different combinations of adhesion molecules and chemokine receptors. The ability of T cells to express these specific combinations of surface molecules is 'imprinted' during initial antigen priming and depends on molecular cues that are governed by the lymph node microenvironment. Memory T cells in peripheral tissues are more resistant to apoptosis than their systemic counterparts, which allows them to survive despite the close proximity to the external environment. Although the mechanism has yet to be identified, this increased resistance to apoptosis is gained when circulating memory T cells enter peripheral tissues. Peripheral memory T cells are mostly of the CD62L − CCR7 − (CC chemokine receptor 7) effector memory T (T EM )-cell phenotype. As the pathogen-specific memory T-cell pool gradually converts to a CD62L + CCR7 + central memory T (T CM )-cell phenotype, there are fewer pathogen-specific cells that are capable of migrating into peripheral tissues. Following clearance of an influenza virus infection, antigen persists in the draining lymph nodes of the lung for several months. This residual antigen contributes to the large number of antigen-specific memory T cells that are present in the lung airways for several months after infection, and the elimination of these antigen depots coincides with the gradual decline in memory T-cell numbers in the lung airways. During a secondary infection, memory T cells in peripheral tissues can be directly activated by pro-inflammatory cytokines to induce effector functions and can interact with antigen-bearing dendritic cells to generate a localized secondary effector T-cell response outside of the draining lymphoid tissue. Together, these actions result in a rapid response at the site of infection that can limit pathogen replication prior to the arrival of secondary effector T cells from the lymph nodes. Vaccination with live viral vectors has proven successful at generating mucosal T-cell memory because effector T cells that had trafficked to antigen-free lymph nodes that drained mucosal sites were imprinted to express homing molecules associated with migration to mucosal tissues. Protein-based immunization strategies using modified cholera toxin as an adjuvant can also induce strong mucosal immunity even when administered at non-mucosal sites. Memory T cells in non-lymphoid tissues provide an important early line of defence against secondary pathogen infection. In this article, the mechanisms involved in the migration, maintenance and function of memory T cells at these peripheral sites are discussed. After the resolution of an immune response, antigen-specific memory T cells persist at many sites in the body. The antigen-specific memory T-cell pool includes memory T cells that preferentially reside in peripheral tissues, such as the skin, gut and lungs, where they provide a first line of defence against secondary pathogen infection. Determining how peripheral memory T cells are regulated is essential for our understanding of host−pathogen interactions and for vaccine development. In this Review, we discuss recent insights into the generation, control and recall of peripheral T-cell memory responses.

Antigen-specific CD8 tissue-resident memory T cells (T cells) persist in the lung following resolution of a respiratory virus infection and provide first-line defense against reinfection. In contrast to other memory T cell populations, such as central memory T cells that circulate between lymph and blood, and effector memory T cells (T cells) that circulate between blood and peripheral tissues, T cells are best defined by their permanent residency in the tissues and their independence from circulatory T cell populations. Consistent with this, we recently demonstrated that CD8 T cells primarily reside within specific niches in the lung (Repair-Associated Memory Depots; RAMD) that normally exclude CD8 T cells. However, it has also been reported that circulating CD8 T cells continuously convert into CD8 T cells in the lung interstitium, helping to sustain T numbers. The relative contributions of these two mechanisms of CD8 T cells maintenance in the lung has been the source of vigorous debate. Here we propose a model in which the majority of CD8 T cells are maintained within RAMD (conventional T ) whereas a small fraction of T are derived from circulating CD8 T cells and maintained in the interstitium. The numbers of both types of T cells wane over time due to declines in both RAMD availability and the overall number of T in the circulation. This model is consistent with most published reports and has important implications for the development of vaccines designed to elicit protective T cell memory in the lung.

B cells provide humoral immunity by differentiating into antibody-secreting plasma cells, a process that requires cellular division and is linked to DNA hypomethylation. Conversely, little is known about how de novo deposition of DNA methylation affects B cell fate and function. Here we show that genetic deletion of the de novo DNA methyltransferases Dnmt3a and Dnmt3b (Dnmt3-deficient) in mouse B cells results in normal B cell development and maturation, but increased cell activation and expansion of the germinal center B cell and plasma cell populations upon immunization. Gene expression is mostly unaltered in naive and germinal center B cells, but dysregulated in Dnmt3-deficient plasma cells. Differences in gene expression are proximal to Dnmt3-dependent DNA methylation and chromatin changes, both of which coincide with E2A and PU.1-IRF composite-binding motifs. Thus, de novo DNA methylation limits B cell activation, represses the plasma cell chromatin state, and regulates plasma cell differentiation. DNA methylation is known to contribute to B cell differentiation, but de novo methylation has not been studied in this context. Here the authors use a conditional Dnmt3a/b knockout mouse to map the function of de novo DNA methylation in B cell differentiation and the development of humoral immunity.

Glycans within human lungs are recognized by many pathogens such as influenza A virus (IAV), yet little is known about their structures. Here we present the first analysis of the N- and O- and glycosphingolipid-glycans from total human lungs, along with histological analyses of IAV binding. The N-glycome of human lung contains extremely large complex-type N-glycans with linear poly-N-acetyllactosamine (PL) [-3Galβ1–4GlcNAcβ1-] n extensions, which are predominantly terminated in α2,3-linked sialic acid. By contrast, smaller N-glycans lack PL and are enriched in α2,6-linked sialic acids. In addition, we observed large glycosphingolipid (GSL)-glycans, which also consists of linear PL, terminating in mainly α2,3-linked sialic acid. Histological staining revealed that IAV binds to sialylated and non-sialylated glycans and binding is not concordant with respect to binding by sialic acid-specific lectins. These results extend our understanding of the types of glycans that may serve as binding sites for human lung pathogens.

Tissue-resident memory T cells (T RM cells) are critical for cellular immunity to respiratory pathogens and reside in both the airways and the interstitium. In the present study, we found that the airway environment drove transcriptional and epigenetic changes that specifically regulated the cytolytic functions of airway T RM cells and promoted apoptosis due to amino acid starvation and activation of the integrated stress response. Comparison of airway T RM cells and splenic effector-memory T cells transferred into the airways indicated that the environment was necessary to activate these pathways, but did not induce T RM cell lineage reprogramming. Importantly, activation of the integrated stress response was reversed in airway T RM cells placed in a nutrient-rich environment. Our data defined the genetic programs of distinct lung T RM cell populations and show that local environmental cues altered airway T RM cells to limit cytolytic function and promote cell death, which ultimately leads to fewer T RM cells in the lung. Kohlmeier and colleagues showed that the airway environment drove transcriptional and epigenetic changes that regulated the cytolytic functions of airway T RM cells and promoted their apoptosis due to amino acid starvation and activation of the integrated stress response.

The long-term physiological consequences of respiratory viral infections, particularly in the aftermath of the COVID-19 pandemic—termed post-acute sequelae of SARS-CoV-2 (PASC)—are rapidly evolving into a major public health concern 1 – 3 . While the cellular and molecular aetiologies of these sequelae are poorly defined, increasing evidence implicates abnormal immune responses 3 – 6 and/or impaired organ recovery 7 – 9 after infection. However, the precise mechanisms that link these processes in the context of PASC remain unclear. Here, with insights from three cohorts of patients with respiratory PASC, we established a mouse model of post-viral lung disease and identified an aberrant immune–epithelial progenitor niche unique to fibroproliferation in respiratory PASC. Using spatial transcriptomics and imaging, we found a central role for lung-resident CD8 + T cell–macrophage interactions in impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Specifically, IFNγ and TNF derived from CD8 + T cells stimulated local macrophages to chronically release IL-1β, resulting in the long-term maintenance of dysplastic epithelial progenitors and lung fibrosis. Notably, therapeutic neutralization of IFNγ + TNF or IL-1β markedly improved alveolar regeneration and pulmonary function. In contrast to other approaches, which require early intervention 10 , we highlight therapeutic strategies to rescue fibrotic disease after the resolution of acute disease, addressing a current unmet need in the clinical management of PASC and post-viral disease. CD8 + T cell–macrophage interactions have a central role in impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia in a mouse model of long COVID.

Viral transmission from infected donors to uninfected recipients is the key event underlying the spread of viral pathogens at the level of a host population. Successful viral transmission from a donor to a recipient depends on several factors including the infectiousness of the donor. Donor infectiousness in turn can depend on the viral kinetics and viral load of the donor, donor behavior and symptoms, and donor immunity. Here, we use a mouse model of murine respirovirus (otherwise known as Sendai virus SeV) infection to quantitatively explore donor determinants of respiratory virus transmission. The experimental transmission studies we analyze are specifically designed to address the effect that pre-existing donor immunity may have on transmission potential by studying SeV transmission from both immunized and control (placebo-immunized) donors to naïve recipients. We specifically focus on the impact of tissue resident memory (TRM) CD8 T cells on donor transmission potential by considering immunization strategies that primarily generate CD8 T cell immunity. Through quantitative analyses of these experiments, we find that pre-existing CD8 TRMs act to reduce donor transmission potential. This finding is in agreement with previous findings and can be in part explained by a reduction in total infection load in immunized donors. However, even once differences in infection load between immunized and control donors are accounted for, immunized donors still have reduced infectiousness relative to control donors. We explore possible reasons for this unexpected pattern using a mathematical model that integrates within-host viral dynamics and between-host transmission occurrences. Analysis of model simulations, along with observations from knock-out experiments, suggests that interferon gamma (IFN- γ ) may be partly responsible for the observed differences in infectiousness between control and immune donors. Future experimental transmission studies should consider measuring IFN- γ levels and its effects when interpreting transmission outcomes in the context of host immunity.

Tissue-resident memory T cells (TRM) in the lungs are pivotal for protection against repeated infection with respiratory viruses. However, the gradual loss of these cells over time and the associated decline in clinical protection represent a serious limit in the development of efficient T cell based vaccines against respiratory pathogens. Here, using an adenovirus expressing influenza nucleoprotein (AdNP), we show that CD8 TRM in the lungs can be maintained for at least 1 year post vaccination. Our results reveal that lung TRM continued to proliferate in situ 8 months after AdNP vaccination. Importantly, this required airway vaccination and antigen persistence in the lung, as non-respiratory routes of vaccination failed to support long-term lung TRM maintenance. In addition, parabiosis experiments show that in AdNP vaccinated mice, the lung TRM pool is also sustained by continual replenishment from circulating memory CD8 T cells that differentiate into lung TRM, a phenomenon not observed in influenza-infected parabiont partners. Concluding, these results demonstrate key requirements for long-lived cellular immunity to influenza virus, knowledge that could be utilized in future vaccine design.

Resident memory CD8 T (TRM) cells in the lung parenchyma (LP) and airways provide heterologous protection against influenza virus challenge. However, scant knowledge exists regarding factors necessary to establish and maintain lung CD8 TRM. Here we demonstrate that, in contrast to mechanisms described for other tissues, airway, and LP CD8 TRM establishment requires cognate antigen recognition in the lung. Systemic effector CD8 T cells could be transiently pulled into the lung in response to localized inflammation, however these effector cells failed to establish tissue residency unless antigen was present in the pulmonary environment. The interaction of effector CD8 T cells with cognate antigen in the lung resulted in increased and prolonged expression of the tissue-retention markers CD69 and CD103, and increased expression of the adhesion molecule VLA-1. The inability of localized inflammation alone to establish lung TRM resulted in decreased viral clearance and increased mortality following heterosubtypic influenza challenge, despite equal numbers of circulating memory CD8 T cells. These findings demonstrate that pulmonary antigen encounter is required for the establishment of lung CD8 TRM and may inform future vaccine strategies to generate robust cellular immunity against respiratory pathogens.

SARS-CoV-2 has caused a historic pandemic of respiratory disease (COVID-19), and current evidence suggests that severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a historic pandemic of respiratory disease (coronavirus disease 2019 [COVID-19]), and current evidence suggests that severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Here, we characterize a mouse model of SARS-CoV-2 infection and find that early CCR2 signaling restricts the viral burden in the lung. We find that a recently developed mouse-adapted SARS-CoV-2 (MA-SARS-CoV-2) strain as well as the emerging B.1.351 variant trigger an inflammatory response in the lung characterized by the expression of proinflammatory cytokines and interferon-stimulated genes. Using intravital antibody labeling, we demonstrate that MA-SARS-CoV-2 infection leads to increases in circulating monocytes and an influx of CD45 + cells into the lung parenchyma that is dominated by monocyte-derived cells. Single-cell RNA sequencing (scRNA-Seq) analysis of lung homogenates identified a hyperinflammatory monocyte profile. We utilize this model to demonstrate that mechanistically, CCR2 signaling promotes the infiltration of classical monocytes into the lung and the expansion of monocyte-derived cells. Parenchymal monocyte-derived cells appear to play a protective role against MA-SARS-CoV-2, as mice lacking CCR2 showed higher viral loads in the lungs, increased lung viral dissemination, and elevated inflammatory cytokine responses. These studies have identified a potential CCR2-monocyte axis that is critical for promoting viral control and restricting inflammation within the respiratory tract during SARS-CoV-2 infection. IMPORTANCE SARS-CoV-2 has caused a historic pandemic of respiratory disease (COVID-19), and current evidence suggests that severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Here, we characterize a mouse model of SARS-CoV-2 infection and find that early CCR2-dependent infiltration of monocytes restricts the viral burden in the lung. We find that SARS-CoV-2 triggers an inflammatory response in the lung characterized by the expression of proinflammatory cytokines and interferon-stimulated genes. Using RNA sequencing and flow cytometry approaches, we demonstrate that SARS-CoV-2 infection leads to increases in circulating monocytes and an influx of CD45 + cells into the lung parenchyma that is dominated by monocyte-derived cells. Mechanistically, CCR2 signaling promoted the infiltration of classical monocytes into the lung and the expansion of monocyte-derived cells. Parenchymal monocyte-derived cells appear to play a protective role against MA-SARS-CoV-2, as mice lacking CCR2 showed higher viral loads in the lungs, increased lung viral dissemination, and elevated inflammatory cytokine responses. These studies have identified that the CCR2 pathway is critical for promoting viral control and restricting inflammation within the respiratory tract during SARS-CoV-2 infection.