Considerable advances have been made in recent years in understanding the generation and function of memory T cells. Memory T cells are typically parsed into discreet subsets based on phenotypic ...definitions that connote distinct roles in immunity. Here we consider new developments in the field and focus on how emerging differences between memory cells with respect to their trafficking, metabolism, epigenetic regulation, and longevity may fail to fit into small groups of “memory subsets.” Rather, the properties of individual memory T cells fall on a continuum within each of these and other parameters. We discuss how this continuum influences the way that the efficacy of vaccination is assessed, as well as the suitability of a memory population for protective immunity.
Memory T cells are typically parsed into discreet subsets based on phenotypic definitions that connote distinct roles in immunity. Jameson and Masopust argue that the conventional subset nomenclature fails to accurately encompass the distribution of functional traits within this diverse population.
Mouse models have enabled breakthroughs in our understanding of the immune system, but it has become increasingly popular to emphasize their shortcomings when translating observations to humans. This ...review provides a brief summary of mouse natural history, husbandry, and the pros and cons of pursuing basic research in mice versus humans. Opportunities are discussed for extending the predictive translational value of mouse research, with an emphasis on exploitation of a "dirty" mouse model that better mimics the diverse infectious history that is typical of most humans.
T Cell Memory: Understanding COVID-19 Jarjour, Nicholas N.; Masopust, David; Jameson, Stephen C.
Immunity,
01/2021, Letnik:
54, Številka:
1
Journal Article
Recenzirano
Odprti dostop
As the SARS-CoV-2 pandemic has progressed, increasing attention has focused on establishing natural and vaccine-induced immunity against this coronavirus and the disease, COVID-19, that it causes. In ...this Primer, we explain the fundamental features of T cell memory and their potential relevance for effective immunity to SARS-CoV-2.
As the SARS-CoV-2 pandemic has progressed, increasing attention has focused on establishing natural and vaccine-induced immunity against this coronavirus and the disease, COVID-19, that it causes. In this Primer, we explain the fundamental features of T cell memory and their potential relevance for effective immunity to SARS-CoV-2.
The CD8+ memory T cell population is heterogeneous, and it is unclear which subset(s) optimally mediate the central goal of the immune system—protection against infection. Here we investigate the ...protective capacities of CD8+ T cell subsets present at the memory stage of the immune response. We show that a population of CD8+ T cells bearing markers associated with effector cells (KLRG1hi, CD27lo, T-bethi, Eomeslo) persisted to the memory phase and provided optimal control of Listeria monocytogenes and vaccinia virus, despite weak recall proliferative responses. After antigen-specific boosting, this population formed the predominant secondary memory subset and maintained superior pathogen control. The effector-like memory subset displayed a distinct pattern of tissue distribution and localization within the spleen, and their enhanced capacity to eliminate Listeria involved specialized utilization of cytolysis. Together, these data suggest that long-lived effector CD8+ T cells are optimal for protective immunity against certain pathogens.
•Effector-like CD27lo CD8+ T cells persist into primary and secondary memory pools•Despite weak expansion, “long-lived effectors” optimally control Listeria and vaccinia•CD27lo memory CD8+ cells show tissue localization favoring rapid pathogen encounter•Cytolysis is selectively utilized by CD27lo memory cells for Listeria control
Invariant natural killer T cells (iNKT cells) can produce copious amounts of interleukin 4 (IL-4) early during infection. However, indirect evidence suggests they may produce this immunomodulatory ...cytokine in the steady state. Through intracellular staining for transcription factors, we have defined three subsets of iNKT cells (NKT1, NKT2 and NKT17) that produced distinct cytokines; these represented diverse lineages and not developmental stages, as previously thought. These subsets exhibited substantial interstrain variation in numbers. In several mouse strains, including BALB/c, NKT2 cells were abundant and were stimulated by self ligands to produce IL-4. In those strains, steady-state IL-4 conditioned CD8(+) T cells to become 'memory-like', increased serum concentrations of immunoglobulin E (IgE) and caused dendritic cells to produce chemokines. Thus, iNKT cell-derived IL-4 altered immunological properties under normal steady-state conditions.
Three subsets of invariant natural killer T (iNKT) cells have been identified, NKT1, NKT2, and NKT17, which produce distinct cytokines when stimulated, but little is known about their localization. ...Here, we have defined the anatomic localization and systemic distribution of these subsets and measured their cytokine production. Thymic NKT2 cells that produced interleukin-4 (IL-4) at steady state were located in the medulla and conditioned medullary thymocytes. NKT2 cells were abundant in the mesenteric lymph node (LN) of BALB/c mice and produced IL-4 in the T cell zone that conditioned other lymphocytes. Intravenous injection of α-galactosylceramide activated NKT1 cells with vascular access, but not LN or thymic NKT cells, resulting in systemic interferon-γ and IL-4 production, while oral α-galactosylceramide activated NKT2 cells in the mesenteric LN, resulting in local IL-4 release. These findings indicate that the localization of iNKT cells governs their cytokine response both at steady state and upon activation.
•IL-4 secreting NKT2 cells are localized in the thymic medulla•Splenic NKT1 cells are in red pulp and NKT2 cells in T cell zone•Intravenous injection of αGalCer activates NKT1 cells in spleen and liver•Oral administration of αGalCer stimulates NKT2 cells in mesenteric LN
Little is known about where iNKT cell subsets are localized, and identifying these cells by current methods can be challenging. Hogquist and colleagues used histocytometry to precisely visualize iNKT cell subsets in tissues and find that the differential location of iNKT cell subsets impacts their cytokine response.
The peripheral naive T cell pool is fairly stable in number, diversity and functional competence in the absence of vigorous immune responses. However, this apparent tranquility is not an intrinsic ...property of T cells but involves continuous tuning of the T cell pool composition by homeostatic signals. In the past decade, studies have revealed that naive T cells rely on combinatorial signals from self-peptide-MHC complexes and interleukin-7 for their physical and functional maintenance. Competition for these factors dictates T cell 'space'. In addition, recent studies show that these and other homeostatic factors are offered to T cells on stromal cell networks, which also serve to guide T cell trafficking in secondary lymphoid organs. Such findings suggest the importance of 'place' in the perception and integration of homeostatic cues for the maintenance and functional tuning of the naive T cell pool.
The adaptive immune response meets the needs of the organism to generate effector cells capable of controlling pathogens but also leads to production of memory cells, which mediate more effective ...protection during rechallenge. In this review, we focus on the generation, maintenance, and function of memory T cells, with a special emphasis on the increasing evidence for great diversity among functional memory T cell subsets.
Self-reactivity was once seen as a potential characteristic of T cells that was eliminated by clonal selection to protect the host from autoimmune pathology. It is now understood that the T cell ...repertoire is in fact broadly self-reactive, even self-centered. The strength with which a T cell reacts to self ligands and the environmental context in which this reaction occurs influence almost every aspect of T cell biology, from development to differentiation to effector function. Here we highlight recent advances and discoveries that relate to T cell self-reactivity, with a particular emphasis on T cell antigen receptor (TCR) signaling thresholds.
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.
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