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The cardinal features of adaptive immunity are memory and antigen-specificity. Since Th2 cells are part of the adaptive immune system, this raises the question of why we need to \"remember\" to repair the wounds that are induced by specific parasites. [...]Th2 cytokines mediate rapid repair while also minimizing the number of incoming parasites via IgE or flushing out intestinal parasites via alterations to gut physiology and excess mucus production.

Macrophages are important immune cells that function in tissue repair during homeostasis and in the innate immune response. Inflammation, which can be triggered by infection, is accompanied by a massive expansion of macrophages in affected tissues. The major source of this increase in resident macrophages has been thought to be hematopoietic stem cells in the bone marrow. However, recent results have shown that the mature differentiated macrophages residing in the affected tissues can themselves proliferate to boost cell numbers. Sieweke and Allen ( 10.1126/science.1242974 ) review what we know about the origin of macrophages and outline the consequences of local macrophage proliferation for the immune response and tissue homeostasis. In many mammalian tissues, mature differentiated cells are replaced by self-renewing stem cells, either continuously during homeostasis or in response to challenge and injury. For example, hematopoietic stem cells generate all mature blood cells, including monocytes, which have long been thought to be the major source of tissue macrophages. Recently, however, major macrophage populations were found to be derived from embryonic progenitors and to renew independently of hematopoietic stem cells. This process may not require progenitors, as mature macrophages can proliferate in response to specific stimuli indefinitely and without transformation or loss of functional differentiation. These findings suggest that macrophages are mature differentiated cells that may have a self-renewal potential similar to that of stem cells.

Key Points Infection with large metazoan parasites (helminths) typically induces a type 2 immune response. Redundancy within the immune system, as well as extensive dialogue between cells of the immune system and non-immune cells, generates enormous complexity. The central player in type 2 immunity is the CD4 + T helper 2 (T H 2) cell, which produces a broad range of cytokines, including interleukin-4 (IL-4) and IL-13, which act on target cells expressing the IL-4 receptor α-chain. Target cells include most cells of the immune system but also local tissue cells such as epithelial cells that line mucosal surfaces. Cells of the innate immune system, such as the recently described 'innate helper cells', can also produce type 2 cytokines. These cells function as effectors during the early stages of infection, but additionally create an environment that favours the induction of T H 2-type responses. T H 2-type responses are initiated by alarm signals from epithelial cells, as well as by specific recognition of helminth products. A strict requirement for dendritic cells in this process has been established. In addition to killing or expelling helminth parasites, type 2 immune responses contribute to rapid tissue repair, and this sometimes leads to fibrosis-related pathology. Many facets of type 2 immunity are consistent with evolutionary origins in wound-healing pathways, a reflection of the capacity of helminth parasites to damage tissue through migration and feeding. T cell dynamics change over time, and T H 2-type responses often decline during chronic helminth infection. Regulatory pathways, including regulatory T cells, restrain pathology and immune responses during infection, and some helminths are able to actively induce the expansion of regulatory populations. Because mammals evolved in the presence of chronic infection, their immune systems may have compensated for the immune dampening effects of helminths. If so, over-reactive responses to innocuous antigens in the absence of infection may contribute to autoimmune disease and allergy. Exciting new studies have uncovered many of the molecules and cell types that contribute to 'type 2' immune responses. Here, Judith Allen and Rick Maizels discuss how these responses are generated and provide protective immunity during helminth infection. The vertebrate immune system has evolved in concert with a broad range of infectious agents, including ubiquitous helminth (worm) parasites. The constant pressure of helminth infections has been a powerful force in shaping not only how immunity is initiated and maintained, but also how the body self-regulates and controls untoward immune responses to minimize overall harm. In this Review, we discuss recent advances in defining the immune cell types and molecules that are mobilized in response to helminth infection. Finally, we more broadly consider how these immunological players are blended and regulated in order to accommodate persistent infection or to mount a vigorous protective response and achieve sterile immunity.

Macrophages populate tissues under homeostatic conditions. Taylor and colleagues discuss the heterogeneity of tissue macrophage populations, and how they contribute to tissue function and immune surveillance. Tissue-resident macrophages are a heterogeneous population of immune cells that fulfill tissue-specific and niche-specific functions. These range from dedicated homeostatic functions, such as clearance of cellular debris and iron processing, to central roles in tissue immune surveillance, response to infection and the resolution of inflammation. Recent studies highlight marked heterogeneity in the origins of tissue macrophages that arise from hematopoietic versus self-renewing embryo-derived populations. We discuss the tissue niche-specific factors that dictate cell phenotype, the definition of which will allow new strategies to promote the restoration of tissue homeostasis. Understanding the mechanisms that dictate tissue macrophage heterogeneity should explain why simplified models of macrophage activation do not explain the extent of heterogeneity seen in vivo .

A defining feature of inflammation is the accumulation of innate immune cells in the tissue that are thought to be recruited from the blood. We reveal that a distinct process exists in which tissue macrophages undergo rapid in situ proliferation in order to increase population density. This inflammatory mechanism occurred during T helper 2 (T(H)2)-related pathologies under the control of the archetypal T(H)2 cytokine interleukin-4 (IL-4) and was a fundamental component of T(H)2 inflammation because exogenous IL-4 was sufficient to drive accumulation of tissue macrophages through self-renewal. Thus, expansion of innate cells necessary for pathogen control or wound repair can occur without recruitment of potentially tissue-destructive inflammatory cells.

Ym1 and RELMα are established effector molecules closely synonymous with Th2-type inflammation and associated pathology. Here, we show that whilst largely dependent on IL-4Rα signaling during a type 2 response, Ym1 and RELMα also have IL-4Rα-independent expression patterns in the lung. Notably, we found that Ym1 has opposing effects on type 2 immunity during nematode infection depending on whether it is expressed at the time of innate or adaptive responses. During the lung migratory stage of Nippostrongylus brasiliensis, Ym1 promoted the subsequent reparative type 2 response but once that response was established, IL-4Rα-dependent Ym1 was important for limiting the magnitude of type 2 cytokine production from both CD4+ T cells and innate lymphoid cells in the lung. Importantly, our study demonstrates that delivery of Ym1 to IL-4Rα deficient animals drives RELMα production and overcomes lung repair deficits in mice deficient in type 2 immunity. Together, Ym1 and RELMα, exhibit time and dose-dependent interactions that determines the outcome of lung repair during nematode infection.

Protein crystals could be targeted therapeutically to treat allergic pathology Charcot-Leyden crystals (CLCs) are protein crystals produced by human eosinophils, immune cells typically associated with allergy and parasitic worm (helminth) infection. These responses involve the “type 2” arm of the immune system, and CLCs are a hallmark of the more severe pathologies that can occur during type 2 inflammation, such as allergic asthma. Although described over 160 years ago, the biological relevance of CLCs to type 2 immunity has remained unknown. On page 751 of this issue, Persson et al. ( 1 ) confirm anecdotal evidence that CLCs are a key feature of severe asthma and chronic rhinosinusitis with nasal polyps. They demonstrate that the crystals, but not the soluble proteins, are powerful promoters of allergic inflammation and can be targeted with crystal-dissolving antibodies to reverse disease symptoms.

The general paradigm is that monocytes are recruited to sites of inflammation and terminally differentiate into macrophages. There has been no demonstration of proliferation of peripherally-derived inflammatory macrophages under physiological conditions. Here we show that proliferation of both bone marrow-derived inflammatory and tissue-resident macrophage lineage branches is a key feature of the inflammatory process with major implications for the mechanisms underlying recovery from inflammation. Both macrophage lineage branches are dependent on M-CSF during inflammation, and thus the potential for therapeutic interventions is marked. Furthermore, these observations are independent of Th2 immunity. These studies indicate that the proliferation of distinct macrophage populations provides a general mechanism for macrophage expansion at key stages during inflammation, and separate control mechanisms are implicated. Monocytes are recruited to sites of damage or infection where they differentiate into inflammatory macrophages. Here the authors demonstrate that, contrary to the prevailing model, these differentiated cells are able to proliferate at sites of inflammation.

The polysaccharide hyaluronan (HA) is an important component of lung extracellular matrix that increases following infection with influenza or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hellman et al. (U. Hellman, E. Rosendal, J. Lehrstrand, J. Henriksson, et al., mBio 15:e01303-24, https://doi.org/10.1128/mbio.01303-24) show that fragmented HA accumulates in the lungs of coronavirus disease 2019 (COVID-19) patients, with systemic levels of HA being associated with reduced lung function 3-6 months after infection. This study provides novel insights into HA's role in COVID-19 pathology and its potential utility as a biomarker for disease severity. However, much remains to be understood about the lung HA matrix in COVID-19 and how it compares to other lung conditions. In particular, the role of HA-binding proteins in organizing HA into a crosslinked network is yet to be fully determined at a molecular level. This knowledge is crucial in understanding the inter-relationships between the structure of the HA matrix and the regulation of the immune response, and thus our ability to target HA therapeutically for improved outcomes in COVID-19.