CD8+HLADR+ Regulatory T Cells Change With Aging: They Increase in Number, but Lose Checkpoint Inhibitory Molecules and Suppressive Function

Yani, Stella Lukas; Keller, Michael; Melzer, Franz Leonard; Weinberger, Birgit; Pangrazzi, Luca; Sopper, Sieghart; Trieb, Klemens; Lobina, Monia; Orrù, Valeria; Fiorillo, Edoardo; Cucca, Francesco; Grubeck‐Loebenstein, Beatrix

doi:10.3389/fimmu.2018.01201

Cited by 24 publications

(17 citation statements)

References 39 publications

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“…We chose several classical phenotype markers of lymphocytes including CD28 (naive marker), CD45RA (naive marker), HLA-DR (activated marker) and CD45RO (memory marker) to reflect host immunity. These phenotype markers are correlated with lymphocyte function and are known to play an important role in many diseases such as infection, tumor, and autoimmune disease [24][25][26][27]. As expected, our data demonstrated that the expression of CD28 on T cells gradually decreased with increasing age and was negatively correlated with their function.…”

Section: Discussionsupporting

confidence: 85%

Establishing immune scoring model based on combination of the number, function, and phenotype of lymphocytes

Tang

Luo

et al. 2020

Aging

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Section: Discussionsupporting

confidence: 85%

Establishing immune scoring model based on combination of the number, function, and phenotype of lymphocytes

Tang

Luo

et al. 2020

Aging

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“…CD8 + HLA-DR + cells suppress in a cell-to cell contact dependent manner, which involves CTLA-4 ( 47 ). Within the CD8 + HLA-DR + Treg cells the CD28 + subpopulation shows higher suppressive capacity compared to their CD28 - counterparts and also expresses higher levels of the checkpoint inhibitory molecules CTLA-4, TIM-3, PD-1 and LAG-3 ( 61 ). Similarities have been found between CD8 + HLA-DR + and CD4 + Foxp3 + Treg with regards to the expression of TIGIT, the chemokine receptors CCR4 and CCR5, the low expression of IL-7R (CD127) and a memory and effector-like phenotype.…”

Section: Subsets Of Regulatory T Cellsmentioning

confidence: 99%

“…Despite the fact that CD8 + HLA-DR + Treg accumulate with age, the expression of CD28 in these cells remains unchanged. CD8 + HLA-DR + Treg cells lose suppressive activity and decrease the production of checkpoint inhibitory molecules in aged individuals ( 61 ).…”

Section: Treg Homeostasis and Function In Agingmentioning

confidence: 99%

The Complex Role of Regulatory T Cells in Immunity and Aging

et al. 2021

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The immune system is a tightly regulated network which allows the development of defense mechanisms against foreign antigens and tolerance toward self-antigens. Regulatory T cells (Treg) contribute to immune homeostasis by maintaining unresponsiveness to self-antigens and suppressing exaggerated immune responses. Dysregulation of any of these processes can lead to serious consequences. Classically, Treg cell functions have been described in CD4+ T cells, but other immune cells also harbour the capacity to modulate immune responses. Regulatory functions have been described for different CD8+ T cell subsets, as well as other T cells such as γδT cells or NKT cells. In this review we describe the diverse populations of Treg cells and their role in different scenarios. Special attention is paid to the aging process, which is characterized by an altered composition of immune cells. Treg cells can contribute to the development of various age-related diseases but they are poorly characterized in aged individuals. The huge diversity of cells that display immune modulatory functions and the lack of universal markers to identify Treg make the expanding field of Treg research complex and challenging. There are still many open questions that need to be answered to solve the enigma of regulatory T cells.

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“…Despite the lack of independent validation, our ability to reproduce previously published healthy age/gender effects on blood immune cells within an identical HD cohort strengthens the probability that CSF data is, likewise, reproducible in future studies. These reproduced age changes in blood include declines in proportion of plDCs with age (42), increases in CD56+ NK cells (43)(44)(45)(46) with age, positive correlation of HLA-DR+ CD8+ T cells (47,48) and HLA-DR+ CD4+ T cells (47) with age, increases in CD4+ T cell/CD3+ T cell ratio with age (49), and increases in proportion of CD3+ T cells (50,51) and proportion of CD4+ T cells with age (51). Reproduced gender differences in blood include a higher presence of B cells in females (52), higher CD4/CD8 ratio in females (53,54), higher proportion of CD8+ T cells in males (54), and higher presence of HLA-DR+ CD4+ T cells and HLA-DR+ CD8+ T cells in males (55).…”

Section: Discussionmentioning

confidence: 99%

Extensive Healthy Donor Age/Gender Adjustments and Propensity Score Matching Reveal Physiology of Multiple Sclerosis Through Immunophenotyping

et al. 2020

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Quantifying cell subpopulations in biological fluids aids in diagnosis and understanding of the mechanisms of injury. Although much has been learned from cerebrospinal fluid (CSF) flow cytometry in neuroimmunological disorders, such as multiple sclerosis (MS), previous studies did not contain enough healthy donors (HD) to derive age- and gender-related normative data and sufficient heterogeneity of other inflammatory neurological disease (OIND) controls to identify MS specific changes.The goals of this blinded training and validation study of MS patients and embedded controls, representing 1,240 prospectively acquired paired CSF/blood samples from 588 subjects was (1) to define physiological age-/gender-related changes in CSF cells, (2) to define/validate cellular abnormalities in blood and CSF of untreated MS through disease duration (DD) and determine which are MS-specific, and (3) to compare effect(s) of low-efficacy (i.e., interferon-beta [IFN-beta] and glatiramer acetate [GA]) and high-efficacy drugs (i.e., natalizumab, daclizumab, and ocrelizumab) on MS-related cellular abnormalities using propensity score matching.Physiological gender differences are less pronounced in the CSF compared to blood, and age-related changes suggest decreased immunosurveillance of CNS by activated HLA-DR+T cells associated with natural aging. Results from patient samples support the concept of MS being immunologically single disease evolving in time. Initially, peripherally activated innate and adaptive immune cells migrate into CSF to form MS lesions. With progression, T cells (CD8+ > CD4+), NK cells, and myeloid dendritic cells are depleted from blood as they continue to accumulate, together with B cells, in the CSF and migrate to CNS tissue, forming compartmentalized inflammation. All MS drugs inhibit non-physiological accumulation of immune cells in the CSF. Although low-efficacy drugs tend to normalize it, high-efficacy drugs overshoot some aspects of CSF physiology, suggesting impairment of CNS immunosurveillance. Comparable inhibition of MS-related CSF abnormalities advocates changes within CNS parenchyma responsible for differences in drug efficacy on MS disability progression.Video summarizing all results may become useful educational tool.

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CD8+HLADR+ Regulatory T Cells Change With Aging: They Increase in Number, but Lose Checkpoint Inhibitory Molecules and Suppressive Function

Cited by 24 publications

References 39 publications

Establishing immune scoring model based on combination of the number, function, and phenotype of lymphocytes

Establishing immune scoring model based on combination of the number, function, and phenotype of lymphocytes

The Complex Role of Regulatory T Cells in Immunity and Aging

Extensive Healthy Donor Age/Gender Adjustments and Propensity Score Matching Reveal Physiology of Multiple Sclerosis Through Immunophenotyping

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