The Influence of Three-dimensional Structure on Naïve T Cell Homeostasis and Aging

Overview

Journal Front Aging

Specialty Geriatrics

Date 2022 Nov 24

PMID 36419548

Authors

Simon Lambert

Wenqiang Cao

Huimin Zhang

Alex Colville

Jie-Yu Liu

Cornelia M Weyand

Jorg J Goronzy

Claire E Gustafson

Affiliations

Soon will be listed here.

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 CD45RA naive cells to a CD45RA 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.

Citing Articles

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

Lorenzo E, Figueroa J, Demirci D, El-Tayyeb F, Huggins B, Illindala M Front Aging. 2024; 5:1376086.

PMID: 38665228 PMC: 11043554. DOI: 10.3389/fragi.2024.1376086.

Aging of lymphoid stromal architecture impacts immune responses.

Lancaster J Semin Immunol. 2023; 70:101817.

PMID: 37572552 PMC: 10929705. DOI: 10.1016/j.smim.2023.101817.

T cell aging and Alzheimer's disease.

Guo L, Li X, Gould T, Wang Z, Cao W Front Immunol. 2023; 14:1154699.

PMID: 37081887 PMC: 10110977. DOI: 10.3389/fimmu.2023.1154699.

References

Gustafson C, Jadhav R, Cao W, Qi Q, Pegram M, Tian L . Immune cell repertoires in breast cancer patients after adjuvant chemotherapy. JCI Insight. 2020; 5(4). PMC: 7101137. DOI: 10.1172/jci.insight.134569. View

Li Y, Masse-Ranson G, Garcia Z, Bruel T, Kok A, Strick-Marchand H . A human immune system mouse model with robust lymph node development. Nat Methods. 2018; 15(8):623-630. DOI: 10.1038/s41592-018-0071-6. View

Courtney A, Shvets A, Lu W, Griffante G, Mollenauer M, Horkova V . CD45 functions as a signaling gatekeeper in T cells. Sci Signal. 2019; 12(604). PMC: 6948007. DOI: 10.1126/scisignal.aaw8151. View

Fang F, Yu M, Cavanagh M, Hutter Saunders J, Qi Q, Ye Z . Expression of CD39 on Activated T Cells Impairs their Survival in Older Individuals. Cell Rep. 2016; 14(5):1218-1231. PMC: 4851554. DOI: 10.1016/j.celrep.2016.01.002. View

Mestas J, Hughes C . Of mice and not men: differences between mouse and human immunology. J Immunol. 2004; 172(5):2731-8. DOI: 10.4049/jimmunol.172.5.2731. View

Yu M, Guo G, Zhang X, Li L, Yang W, Bollag R . Fibroblastic reticular cells of the lymphoid tissues modulate T cell activation threshold during homeostasis via hyperactive cyclooxygenase-2/prostaglandin E axis. Sci Rep. 2017; 7(1):3350. PMC: 5469856. DOI: 10.1038/s41598-017-03459-5. View

MERKENSCHLAGER M, Beverley P . Evidence for differential expression of CD45 isoforms by precursors for memory-dependent and independent cytotoxic responses: human CD8 memory CTLp selectively express CD45RO (UCHL1). Int Immunol. 1989; 1(4):450-9. DOI: 10.1093/intimm/1.4.450. View

Preussner M, Schreiner S, Hung L, Porstner M, Jack H, Benes V . HnRNP L and L-like cooperate in multiple-exon regulation of CD45 alternative splicing. Nucleic Acids Res. 2012; 40(12):5666-78. PMC: 3384337. DOI: 10.1093/nar/gks221. View

Knoblich K, Cruz Migoni S, Siew S, Jinks E, Kaul B, Jeffery H . The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation. PLoS Biol. 2018; 16(9):e2005046. PMC: 6122729. DOI: 10.1371/journal.pbio.2005046. View

10.

Gorgoulis V, Adams P, Alimonti A, Bennett D, Bischof O, Bishop C . Cellular Senescence: Defining a Path Forward. Cell. 2019; 179(4):813-827. DOI: 10.1016/j.cell.2019.10.005. View

11.

Windhagen A, Sonmez D, Hornig-Do H, Kalinowsky A, Schwinzer R . Altered CD45 isoform expression in C77G carriers influences cytokine responsiveness and adhesion properties of T cells. Clin Exp Immunol. 2007; 150(3):509-17. PMC: 2219380. DOI: 10.1111/j.1365-2249.2007.03508.x. View

12.

Goronzy J, Weyand C . Mechanisms underlying T cell ageing. Nat Rev Immunol. 2019; 19(9):573-583. PMC: 7584388. DOI: 10.1038/s41577-019-0180-1. View

13.

Okoye A, Rohankhedkar M, Konfe A, Abana C, Reyes M, Clock J . Effect of IL-7 Therapy on Naive and Memory T Cell Homeostasis in Aged Rhesus Macaques. J Immunol. 2015; 195(9):4292-305. PMC: 4617185. DOI: 10.4049/jimmunol.1500609. View

14.

Wagar L, Salahudeen A, Constantz C, Wendel B, Lyons M, Mallajosyula V . Modeling human adaptive immune responses with tonsil organoids. Nat Med. 2021; 27(1):125-135. PMC: 7891554. DOI: 10.1038/s41591-020-01145-0. View

15.

Siegert S, Huang H, Yang C, Scarpellino L, Carrie L, Essex S . Fibroblastic reticular cells from lymph nodes attenuate T cell expansion by producing nitric oxide. PLoS One. 2011; 6(11):e27618. PMC: 3215737. DOI: 10.1371/journal.pone.0027618. View

16.

Tungatt K, Bianchi V, Crowther M, Powell W, Schauenburg A, Trimby A . Antibody stabilization of peptide-MHC multimers reveals functional T cells bearing extremely low-affinity TCRs. J Immunol. 2014; 194(1):463-74. PMC: 4273996. DOI: 10.4049/jimmunol.1401785. View

17.

White J, Cross E, Burchill M, Danhorn T, McCarter M, Rosen H . Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner. Nat Commun. 2016; 7:11291. PMC: 4844673. DOI: 10.1038/ncomms11291. View

18.

Lissina A, Ladell K, Skowera A, Clement M, Edwards E, Seggewiss R . Protein kinase inhibitors substantially improve the physical detection of T-cells with peptide-MHC tetramers. J Immunol Methods. 2008; 340(1):11-24. PMC: 3052435. DOI: 10.1016/j.jim.2008.09.014. View

19.

Link A, Vogt T, Favre S, Britschgi M, Acha-Orbea H, Hinz B . Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat Immunol. 2007; 8(11):1255-65. DOI: 10.1038/ni1513. View

20.

Masters A, Hall A, Bartley J, Keilich S, Lorenzo E, Jellison E . Assessment of Lymph Node Stromal Cells as an Underlying Factor in Age-Related Immune Impairment. J Gerontol A Biol Sci Med Sci. 2019; 74(11):1734-1743. PMC: 6777091. DOI: 10.1093/gerona/glz029. View