Memory-phenotype CD8
T cells exist in substantial numbers within hosts that have not been exposed to either foreign antigen or overt lymphopenia. These antigen-inexperienced memory-phenotype T cells ...can be divided into two major subsets: 'innate memory' T cells and 'virtual memory' T cells. Although these two subsets are nearly indistinguishable by surface markers alone, notable developmental and functional differences exist between the two subsets, which suggests that they represent distinct populations. In this Opinion article, we review the available literature on each subset, highlighting the key differences between these populations. Furthermore, we suggest a unifying model for the categorization of antigen-inexperienced memory-phenotype CD8
T cells.
Virtual memory cells (VM) are an antigen-specific, memory phenotype CD8 T-cell subset found in lymphoreplete, unchallenged mice. Previous studies indicated that VM cells were the result of ...homeostatic proliferation (HP) resembling the proliferation observed in a lymphopenic environment. Here we demonstrate that HP is ongoing in lymphoreplete mice, the degree of which is dictated by the number of naive CD8 T cells with a sufficiently high affinity for self-antigen interacting with peripheral IL-15. VM cell transcriptional profiles suggest a capacity to mediate protective immunity via antigen non-specific bystander killing, a function we show is dependent on IL-15. Finally, we show a VM-like population of human cells that accumulate with age and traffic to the liver, displaying phenotypic and functional attributes consistent with the bystander protective functions of VM cells identified in the mouse. These data identify developmental and functional attributes of VM cells, including their likely role in protective immunity.
Purpose: Social contact is known to be vital for older adults' mental and physical health but, because communication impairments often co-occur with other types of disability, it is difficult to ...generalize about the relative impact of a communication impairment on the social relationships of older adults. Specific aims of the study were to examine whether the severity of a communication impairment was associated with a range of social measures and to examine the association between these characteristics and psychological well-being. Method: Community-dwelling older adults ranging in age from 65 to 94 were recruited for the study of Communication, Health, Aging, Relationship Types and Support. The sample included 240 participants with communication disorders arising from a variety of etiologies including hearing impairment, voice disorders, head and neck cancer, and neurologic disease, as well as older adults without a communication disorder. Results: Communication impairment was a significant independent predictor for key characteristics of social relationships, including the number of friends in the social network, two types of social support, the frequency of social participation, and social self-efficacy. Communication impairment was also a significant predictor for higher levels of loneliness and depression. In addition, two distinct pathways between communication impairment and psychological well-being were identified, with social self-efficacy and reassurance of worth as mediators. Conclusions: Even after controlling for age, gender, health, and disability, communication impairment is a significant independent predictor for key aspects of the social function of older adults and demonstrates two distinct pathways to loneliness and depression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
The authors describe the actions that take place in T cells because of their amazing capacity to proliferate and adopt functional roles aimed at clearing a host of an infectious agent. There is a ...drastic decline in the T cell population once the primary response is over and the infection is terminated. What remains afterward is a population of T cells with a "memory" for the pathogen they had just taken part in controlling. These remaining T cells, after the collapse of the primary response, are altered in their functional abilities. The authors further describe in this review that it does not incorporate all of the possible permutations that can and do exist in T cell responses generated in the real world, that is, the response that happens when everything is working exactly as it should, culminating in effective, long-lived memory against an infectious pathogen. While idealized responses do occur in nature, the most interesting and productive ends of the T cell research spectrum focus on what happens when things go wrong and why. Examining these extremes of immune dysfunction, within the framework of an idealized response, promises to be a fruitful future source of investigation with both basic and clinical relevance.
Various populations of memory phenotype CD8(+) T cells have been described over the last 15-20 y, all of which possess elevated effector functions relative to naive phenotype cells. Using a technique ...for isolating Ag-specific cells from unprimed hosts, we recently identified a new subset of cells, specific for nominal Ag, but phenotypically and functionally similar to memory cells arising as a result of homeostatic proliferation. We show in this study that these virtual memory (VM) cells are independent of previously identified innate memory cells, arising as a result of their response to IL-15 trans presentation by lymphoid tissue-resident CD8α(+) dendritic cells in the periphery. The absence of IL-15, CD8(+) T cell expression of either CD122 or eomesodermin or of CD8a(+) dendritic cells all lead to the loss of VM cells in the host. Our results show that CD8(+) T cell homeostatic expansion is an active process within the nonlymphopenic environment, is mediated by IL-15, and produces Ag-inexperienced memory cells that retain the capacity to respond to nominal Ag with memory-like function. Preferential engagement of these VM T cells into a vaccine response could dramatically enhance the rate by which immune protection develops.
Since its discovery over three decades ago, signal transducer and activator of transcription 1 (STAT1) has been extensively studied as a central mediator for interferons (IFNs) signaling and ...antiviral defense. Here, using genetic and biochemical assays, we unveil Thr
as a conserved IFN-independent phosphorylation switch in Stat1, which restricts IFN signaling and promotes innate inflammatory responses following the recognition of the bacterial-derived toxin lipopolysaccharide (LPS). Genetically engineered mice expressing phospho-deficient threonine748-to-alanine (T748A) mutant Stat1 are resistant to LPS-induced lethality. Of note, T748A mice exhibited undisturbed IFN signaling, as well as total expression of Stat1. Further, the T748A point mutation of Stat1 recapitulates the safeguard effect of the genetic ablation of
following LPS-induced lethality, indicating that the Thr
phosphorylation contributes inflammatory functionalities of Stat1. Mechanistically, LPS-induced Toll-like receptor 4 endocytosis activates a cell-intrinsic IκB kinase-mediated Thr
phosphorylation of Stat1, which promotes macrophage inflammatory response while restricting the IFN and anti-inflammatory responses. Depletion of macrophages restores the sensitivity of the T748A mice to LPS-induced lethality. Together, our study indicates a phosphorylation-dependent modular functionality of Stat1 in innate immune responses: IFN phospho-tyrosine dependent and inflammatory phospho-threonine dependent. Better understanding of the Thr
phosphorylation of Stat1 may uncover advanced pharmacologically targetable molecules and offer better treatment modalities for sepsis, a disease that claims millions of lives annually.
To investigate the association of stair climbing difficulty and stair climbing frequency with the risk of all-cause mortality over 13 years in adults with or at high risk for knee OA.
We used data ...from the Osteoarthritis Initiative (OAI), a prospective cohort study of community-dwelling adults with or at high risk for symptomatic knee OA. The exposures were stair climbing difficulty and frequency, assessed at baseline using self-report questionnaires. The outcome was all-cause mortality, assessed from baseline through 13 years of follow-up. Kaplan-Meier survival curves and Cox proportional hazards regression were used to investigate the association between stair climbing exposures and all-cause mortality.
Three hundred seven (6.81%) and 310 (6.84%) participants in the difficulty and frequency samples, respectively, died during 13 years of follow-up. Those who were limited in any capacity in terms of their stair climbing ability had 54% to 84% greater hazard of all-cause mortality, and those who climbed at least 7 flights of stairs per week had 38% lower hazard of all-cause mortality.
Adults with or at high risk for knee OA who report difficulty with climbing stairs or who infrequently use stairs are at greater hazard of all-cause mortality. Stair climbing difficulty and frequency are simple to collect and changes may occur early in OA progression, allowing for early intervention. Brief questions about stair climbing behaviors can serve as a functional vital sign within the clinician's toolbox.
PDF
