The influence of three-dimensional structure on naïve T cell homeostasis and aging

Abstract

A breakdown in cellular homeostasis is thought to drive naïve T cell aging, however the link between naïve T cell homeostasis and aging in humans is poorly understood. To better address this, we developed a lymphoid organoid system that maintains resting naïve T cells for more than 2 weeks, in conjunction with high CD45RA expression. Deep phenotypic characterization of naïve T cells across age identified reduced CD45RA density as a hallmark of aging. A conversion from CD45RAhigh naive cells to a CD45RAlow phenotype was reproduced within our organoid system by structural breakdown, but not by stromal cell aging or reduced lymphocyte density, and mediated by alternative CD45 splicing. Together, these data suggest that external influences within the lymph node microenvironment may cause phenotypic conversion of naïve T cells in older adults.

Unraveling the association between major depressive disorder and senescent biomarkers in immune cells of older adults: a single-cell phenotypic analysis

“…Our findings suggest that MDD in older adults is associated with increased iSC characteristics in different immune cell subsets, accompanied by dysregulation of immunoinflammatory control at the mRNA level within these subsets. Finally, our findings support the notion that an “aged” and dysregulated immune system has the potential to significantly contribute to the elevated pro-inflammatory state associated with MDD ( Diniz et al, 2016 ), the neuroprogressive nature of this disorder, and its long-term adverse outcomes ( Morris et al, 2019 ; Lambert et al, 2022 ).…”

“…Age-associated changes in immune function, often referred to as immunosenescence, are evident in the innate and adaptive immune systems. For example, immunosenescence of T cells is characterized by expression of surface markers of exhaustion [PD-1 ( Janelle et al, 2021 )], inhibition [CD57 ( Brenchley et al, 2003 ) and KLRG-1 ( Henson and Akbar, 2009 )], decreased expression of co-stimulatory molecules [CD27 and CD28 ( Plunkett et al, 2007 )], CD45RA re-expression on memory cells ( Henson et al, 2012 ), diminished CD45RA expression on naïve cells ( Lambert et al, 2022 ), and p16 overexpression ( Janelle et al, 2021 ). Many of these markers and functional changes, however, are integral to homeostatic mechanisms and physiological responses and are therefore not exclusively indicative of cellular senescence ( Brenchley et al, 2003 ; Plunkett et al, 2007 ; Henson and Akbar, 2009 ; Henson et al, 2012 ; Janelle et al, 2021 ; Lambert et al, 2022 ).…”

“…For example, immunosenescence of T cells is characterized by expression of surface markers of exhaustion [PD-1 ( Janelle et al, 2021 )], inhibition [CD57 ( Brenchley et al, 2003 ) and KLRG-1 ( Henson and Akbar, 2009 )], decreased expression of co-stimulatory molecules [CD27 and CD28 ( Plunkett et al, 2007 )], CD45RA re-expression on memory cells ( Henson et al, 2012 ), diminished CD45RA expression on naïve cells ( Lambert et al, 2022 ), and p16 overexpression ( Janelle et al, 2021 ). Many of these markers and functional changes, however, are integral to homeostatic mechanisms and physiological responses and are therefore not exclusively indicative of cellular senescence ( Brenchley et al, 2003 ; Plunkett et al, 2007 ; Henson and Akbar, 2009 ; Henson et al, 2012 ; Janelle et al, 2021 ; Lambert et al, 2022 ). Infection models have also demonstrated that aged human T-cells may exhibit characteristics of senescence such as p21 gene expression, enrichment for SASP genes, and increased SA-β-gal following replicative stress but show repressed histone expression ( Kim et al, 2021 ).…”

T cell aging and Alzheimer’s disease

“…Age-associated transcriptional factors and microRNA network changes account for those differentiation states ( 9 , 13 , 60 , 62 – 64 ). A phenotypically unique subset of “young naïve T cells” –CD45RA high CD27 high CD38 + CD25 neg –is lost with age ( 65 ). More differentiated states in aged naïve T cells imply less effector plasticity.…”