Sensing and alarm function of resident memory CD8 + T cells
TL;DR: This work identifies the following additional function for memory CD8+ T cells that persist at front-line sites of microbial exposure: to serve as local sensors of previously encountered antigens that precipitate innate-like alarm signals and draw circulating memory T cells into the tissue.
Abstract: Tissue-resident effector memory T cells respond rapidly after reencountering antigen. Masopust and colleagues show that memory CD8+ T cells also induce the release of chemokines, then recruit more memory cells to the site of infection.
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TL;DR: This review focuses on recent advances in understanding how the chemokine system orchestrates immune cell migration and positioning at the organismic level in homeostasis, in acute inflammation, and during the generation and regulation of adoptive primary and secondary immune responses in the lymphoid system and peripheral nonlymphoid tissue.
Abstract: Chemokines are chemotactic cytokines that control the migratory patterns and positioning of all immune cells. Although chemokines were initially appreciated as important mediators of acute inflammation, we now know that this complex system of approximately 50 endogenous chemokine ligands and 20 G protein–coupled seven-transmembrane signaling receptors is also critical for the generation of primary and secondary adaptive cellular and humoral immune responses. Recent studies demonstrate important roles for the chemokine system in the priming of naive T cells, in cell fate decisions such as effector and memory cell differentiation, and in regulatory T cell function. In this review, we focus on recent advances in understanding how the chemokine system orchestrates immune cell migration and positioning at the organismic level in homeostasis, in acute inflammation, and during the generation and regulation of adoptive primary and secondary immune responses in the lymphoid system and peripheral nonlymphoid tissue.
1,475 citations
Cites background from "Sensing and alarm function of resid..."
...This results in robust local production of chemokines, such as CXCL9, which recruits circulating memory CD8+ T cells independent of their antigen specificity (217)....
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TL;DR: It is shown that standard laboratory mouse husbandry has profound effects on the immune system and that environmental changes produce mice with immune systems closer to those of adult humans, and suggested that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modelling immunological events in free-living organisms, including humans.
Abstract: Our current understanding of immunology was largely defined in laboratory mice, partly because they are inbred and genetically homogeneous, can be genetically manipulated, allow kinetic tissue analyses to be carried out from the onset of disease, and permit the use of tractable disease models. Comparably reductionist experiments are neither technically nor ethically possible in humans. However, there is growing concern that laboratory mice do not reflect relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside. Laboratory mice live in abnormally hygienic specific pathogen free (SPF) barrier facilities. Here we show that standard laboratory mouse husbandry has profound effects on the immune system and that environmental changes produce mice with immune systems closer to those of adult humans. Laboratory mice--like newborn, but not adult, humans--lack effector-differentiated and mucosally distributed memory T cells. These cell populations were present in free-living barn populations of feral mice and pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting that the environment is involved in the induction of these cells. Altering the living conditions of mice profoundly affected the cellular composition of the innate and adaptive immune systems, resulted in global changes in blood cell gene expression to patterns that more closely reflected the immune signatures of adult humans rather than neonates, altered resistance to infection, and influenced T-cell differentiation in response to a de novo viral infection. These data highlight the effects of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modelling immunological events in free-living organisms, including humans.
793 citations
TL;DR: This review will summarize current knowledge of Trm cell ontogeny, regulation, maintenance, and function and will highlight technical considerations for studying this population.
734 citations
Cites background from "Sensing and alarm function of resid..."
...…(Gebhardt et al., 2009;Masopust et al., 2010), lymphatic canulation (Mackay et al., 1990), transfers of labeled T cells (Hofmann and Pircher, 2011; Masopust et al., 2004; 2010), and/or parabiotic surgery (Iijima and Iwasaki, 2014; Jiang et al., 2012; Klonowski et al., 2004; Schenkel et al., 2013)....
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...And when the vasculature of two mice was conjoined via parabiotic surgery, T cells did not equilibrate between the skin epidermis, female reproductive tract, or lung of each mouse (Iijima and Iwasaki, 2014; Jiang et al., 2012; Schenkel et al., 2013; Teijaro et al., 2011)....
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TL;DR: This Review discusses the major advances and the emerging concepts in this field, summarizes what is known about the differentiation and the protective functions of tissue-resident memory T cells in different tissues in the body and highlights key unanswered questions.
Abstract: T cells have crucial roles in protection against infection and cancer. Although the trafficking of memory T cells around the body is integral to their capacity to provide immune protection, studies have shown that specialization of some memory T cells into unique tissue-resident subsets gives the host enhanced regional immunity. In recent years, there has been considerable progress in our understanding of tissue-resident T cell development and function, revealing mechanisms for enhanced protective immunity that have the potential to influence rational vaccine design. This Review discusses the major advances and the emerging concepts in this field, summarizes what is known about the differentiation and the protective functions of tissue-resident memory T cells in different tissues in the body and highlights key unanswered questions.
709 citations
TL;DR: A core transcriptional profile within the CD69+ subset of memory CD4+ and CD8+ T cells in lung and spleen that is distinct from that of CD69- TEM cells in tissues and circulation is identified, providing a unifying signature for human TRM and a blueprint for designing tissue-targeted immunotherapies.
701 citations
Cites background from "Sensing and alarm function of resid..."
...In mice, CD69 is expressed by the majority of CD4 and CD8 TRMs in multiple sites (Jiang et al., 2012; Masopust et al., 2006; Schenkel et al., 2013; Teijaro et al., 2011), while CD103 is only expressed by certain subsets of CD8 TRM (Bergsbaken and Bevan, 2015; Mueller and Mackay, 2016) and not significantly by CD4 TRM (Thom et al....
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...In mice, CD69 is expressed by the majority of CD4+ and CD8+ TRMs in multiple sites (Jiang et al., 2012; Masopust et al., 2006; Schenkel et al., 2013; Teijaro et al., 2011), while CD103 is only expressed by certain subsets of CD8+ TRM (Bergsbaken and Bevan, 2015; Mueller and Mackay, 2016) and not…...
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References
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TL;DR: New insights into innate immunity are changing the way the way the authors think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.
10,685 citations
TL;DR: It is shown that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets, which are named central memory (TCM) and effector memory (TEM).
Abstract: Naive T lymphocytes travel to T-cell areas of secondary lymphoid organs in search of antigen presented by dendritic cells. Once activated, they proliferate vigorously, generating effector cells that can migrate to B-cell areas or to inflamed tissues. A fraction of primed T lymphocytes persists as circulating memory cells that can confer protection and give, upon secondary challenge, a qualitatively different and quantitatively enhanced response. The nature of the cells that mediate the different facets of immunological memory remains unresolved. Here we show that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets. CCR7- memory cells express receptors for migration to inflamed tissues and display immediate effector function. In contrast, CCR7+ memory cells express lymph-node homing receptors and lack immediate effector function, but efficiently stimulate dendritic cells and differentiate into CCR7- effector cells upon secondary stimulation. The CCR7+ and CCR7- T cells, which we have named central memory (TCM) and effector memory (TEM), differentiate in a step-wise fashion from naive T cells, persist for years after immunization and allow a division of labour in the memory response.
5,537 citations
TL;DR: This review addresses the heterogeneity of TCM and TEM, their differentiation stages, and the current models for their generation and maintenance in humans and mice.
Abstract: The memory T cell pool functions as a dynamic repository of antigen-experienced T lymphocytes that accumulate over the lifetime of the individual. Recent studies indicate that memory T lymphocytes contain distinct populations of central memory (TCM) and effector memory (TEM) cells characterized by distinct homing capacity and effector function. This review addresses the heterogeneity of TCM and TEM, their differentiation stages, and the current models for their generation and maintenance in humans and mice.
2,881 citations
TL;DR: In response to viral or bacterial infection, antigen-specific CD8 T cells migrated to nonlymphoid tissues and were present as long-lived memory cells, pointing to the existence of a population of extralymphoid effector memory T cells poised for immediate response to infection.
Abstract: Many intracellular pathogens infect a broad range of host tissues, but the importance of T cells for immunity in these sites is unclear because most of our understanding of antimicrobial T cell responses comes from analyses of lymphoid tissue. Here, we show that in response to viral or bacterial infection, antigen-specific CD8 T cells migrated to nonlymphoid tissues and were present as long-lived memory cells. Strikingly, CD8 memory T cells isolated from nonlymphoid tissues exhibited effector levels of lytic activity directly ex vivo, in contrast to their splenic counterparts. These results point to the existence of a population of extralymphoid effector memory T cells poised for immediate response to infection.
1,882 citations
TL;DR: It is proposed that TCM and TEM do not necessarily represent distinct subsets, but are part of a continuum in a linear naive → effector → TEM → TCM differentiation pathway.
Abstract: Memory CD8 T cells can be divided into two subsets, central (TCM) and effector (TEM), but their lineage relationships and their ability to persist and confer protective immunity are not well understood. Our results show that TCM have a greater capacity than TEM to persist in vivo and are more efficient in mediating protective immunity because of their increased proliferative potential.We also demonstrate that, following antigen clearance, TEM convert to TCM and that the duration of this differentiation is programmed within the first week after immunization.We propose that TCM and TEM do not necessarily represent distinct subsets, but are part of a continuum in a linear naive → effector → TEM → TCM differentiation pathway.
1,842 citations