Type 2 diabetes is associated with the accumulation of senescent T cells

Lau, Edward Yan Ming; Carroll, Elizabeth C.; Callender, Lauren A.; Hood, Gillian; Berryman, Victoria; Pattrick, Melanie; Finer, Sarah; Hitman, GA; Ackland, Gareth L.; Henson, Sian M.

doi:10.1111/cei.13344

Cited by 82 publications

(81 citation statements)

References 48 publications

(70 reference statements)

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“…The evidence, therefore, for an autoimmune pathogenesis in DR is relatively limited (205). Interestingly, in the context of premature aging of endothelial cells in DR (see above), there also appears to be an accumulation of senescent T cells in the circulation of T2D patients with impaired glucose metabolism (206). Most recently, in a prospective pilot study, increased numbers of circulating neutrophilic leukocytes with a reduced number of T cells during the development and progression of DR was observed (207).…”

Section: Diabetic Retinopathy-is There a Role For Adaptive Immunity?mentioning

confidence: 99%

The Role of Inflammation in Diabetic Retinopathy

2020

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Inflammation is central to pathogenic processes in diabetes mellitus and the metabolic syndrome and particularly implicates innate immunity in the development of complications. Inflammation is a primary event in Type 1 diabetes where infectious (viral) and/or autoimmune processes initiate disease; in contrast, chronic inflammation is typical in Type 2 diabetes and is considered a sequel to increasing insulin resistance and disturbed glucose metabolism. Diabetic retinopathy (DR) is perceived as a vascular and neurodegenerative disease which occurs after some years of poorly controlled diabetes. However, many of the clinical features of DR are late events and reflect the nature of the retinal architecture and its cellular composition. Retinal microvascular disease is, in fact, an early event pathogenetically, induced by low grade, persistent leukocyte activation which causes repeated episodes of capillary occlusion and, progressive, attritional retinal ischemia. The later, overt clinical signs of DR are a consequence of the retinal ischemia. Metabolic dysregulation involving both lipid and glucose metabolism may lead to leukocyte activation. On a molecular level, we have shown that macrophage-restricted protein tyrosine phosphatase 1B (PTP1B) is a key regulator of inflammation in the metabolic syndrome involving insulin resistance and it is possible that PTP1B dysregulation may underlie retinal microvascular disease. We have also shown that adherent CCR5 + CD11b + monocyte macrophages appear to be selectively involved in retinal microvascular occlusion. In this review, we discuss the relationship between early leukocyte activation and the later features of DR, common pathogenetic processes between diabetic microvascular disease and other vascular retinopathies, the mechanisms whereby leukocyte activation is induced in hyperglycemia and dyslipidemia, the signaling mechanisms involved in diabetic microvascular disease, and possible interventions which may prevent these retinopathies. We also address a possible role for adaptive immunity in DR. Although significant improvements in treatment of DR have been made with intravitreal anti-VEGF therapy, a sizeable proportion of patients, particularly with sight-threatening macular edema, fail to respond. Alternative therapies targeting inflammatory processes may offer an advantage.

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Section: Diabetic Retinopathy-is There a Role For Adaptive Immunity?mentioning

confidence: 99%

The Role of Inflammation in Diabetic Retinopathy

2020

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“…Owing to impaired metabolism, shortened telomeres and aberrant intracellular signaling ( 33 , 164 , 165 ), reduced proliferation, cytokine production, cytotoxicity and migration are examples of some of the functional impairments that have been reported for T cells isolated from older adults and those with inflammatory co-morbidities ( 33 , 166 , 167 ). The peripheral T cell pools of these adults are enriched with functionally exhausted (TIGIT + , PD-1 + ), highly activated (TIGIT + HLA-DR + CD38 + ), senescent (CD28 − 57 + , CCR7 − 45RA + ) and terminally differentiated (CD27 − 28 − ) CD4 + or CD8 + T cells ( 33 , 168 – 170 ). The most profound changes are witnessed within the CD8 + T cell subset, with the accumulation of CD8 + 28 − T cells of particular significance ( 171 ).…”

Section: Pathogen Eliminationmentioning

confidence: 99%

Immunesenescence: A Predisposing Risk Factor for the Development of COVID-19?

Hazeldine

Lord

2020

Front. Immunol.

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Bearing a strong resemblance to the phenotypic and functional remodeling of the immune system that occurs during aging (termed immunesenescence), the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 2019 (COVID-19), is characterized by an expansion of inflammatory monocytes, functional exhaustion of lymphocytes, dysregulated myeloid responses and the presence of highly activated senescent T cells. Alongside advanced age, male gender and pre-existing co-morbidities [e.g., obesity and type 2 diabetes (T2D)] are emerging as significant risk factors for COVID-19. Interestingly, immunesenescence is more profound in males when compared to females, whilst accelerated aging of the immune system, termed premature immunesenescence, has been described in obese subjects and T2D patients. Thus, as three distinct demographic groups with an increased susceptibility to COVID-19 share a common immune profile, could immunesenescence be a generic contributory factor in the development of severe COVID-19? Here, by focussing on three key aspects of an immune response, namely pathogen recognition, elimination and resolution, we address this question by discussing how immunesenescence may weaken or exacerbate the immune response to SARS-CoV-2. We also highlight how aspects of immunesenescence could render potential COVID-19 treatments less effective in older adults and draw attention to certain therapeutic options, which by reversing or circumventing certain features of immunesenescence may prove to be beneficial for the treatment of groups at high risk of severe COVID-19.

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“…The mechanistic link between ELA and T2D is re-enforced by the immune disturbances reported. Patients with T2D have a larger number senescent CD8+ cytotoxic T cells and higher levels of systemic inflammation [109,110] that may explain the higher incidence of viral and bacterial infections in diabetic patients [111].…”

Section: Early Life Origins Of Covid Co-morbiditiesmentioning

confidence: 99%

The COVID-19 Pandemic: Does Our Early Life Environment, Life Trajectory and Socioeconomic Status Determine Disease Susceptibility and Severity?

Holuka

Merz

Fernandes

et al. 2020

IJMS

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A poor socioeconomic environment and social adversity are fundamental determinants of human life span, well-being and health. Previous influenza pandemics showed that socioeconomic factors may determine both disease detection rates and overall outcomes, and preliminary data from the ongoing coronavirus disease (COVID-19) pandemic suggests that this is still true. Over the past years it has become clear that early-life adversity (ELA) plays a critical role biasing the immune system towards a pro-inflammatory and senescent phenotype many years later. Cytotoxic T-lymphocytes (CTL) appear to be particularly sensitive to the early life social environment. As we understand more about the immune response to SARS-CoV-2 it appears that a functional CTL (CD8+) response is required to clear the infection and COVID-19 severity is increased as the CD8+ response becomes somehow diminished or exhausted. This raises the hypothesis that the ELA-induced pro-inflammatory and senescent phenotype may play a role in determining the clinical course of COVID-19, and the convergence of ELA-induced senescence and COVID-19 induced exhaustion represents the worst-case scenario with the least effective T-cell response. If the correct data is collected, it may be possible to separate the early life elements that have made people particularly vulnerable to COVID-19 many years later. This will, naturally, then help us identify those that are most at risk from developing the severest forms of COVID-19. In order to do this, we need to recognize socioeconomic and early-life factors as genuine medically and clinically relevant data that urgently need to be collected. Finally, many biological samples have been collected in the ongoing studies. The mechanisms linking the early life environment with a defined later-life phenotype are starting to be elucidated, and perhaps hold the key to understanding inequalities and differences in the severity of COVID-19.

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Type 2 diabetes is associated with the accumulation of senescent T cells

Cited by 82 publications

References 48 publications

The Role of Inflammation in Diabetic Retinopathy

The Role of Inflammation in Diabetic Retinopathy

Immunesenescence: A Predisposing Risk Factor for the Development of COVID-19?

The COVID-19 Pandemic: Does Our Early Life Environment, Life Trajectory and Socioeconomic Status Determine Disease Susceptibility and Severity?

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