Exploring Lymph Node Stroma Ageing: Immune Implications and Future Directions

Overview

Journal Aging Cell

Specialties Cell Biology
Geriatrics

Date 2025 Feb 15

PMID 39954244

Authors

Yu Yang Ng

Andy Tay

Affiliations

Soon will be listed here.

Abstract

Ageing is an inevitable biological process that impacts the immune system, leading to immunosenescence and inflammaging, which contribute to increased susceptibility to infections, autoimmune diseases and cancers in individuals over the age of 65. This review focuses on the ageing of lymph node stromal cells (LNSCs), which are crucial for maintaining lymph node (LN) structure and function. Age-related changes in LNs, such as fibrosis and lipomatosis, disrupt the LN architecture and reduce immune cell recruitment and function, impairing immune responses to infections and vaccinations. The review discusses the structural and functional decline of various LNSC subsets, including fibroblastic reticular cells (FRCs), lymphatic endothelial cells (LECs) and blood endothelial cells (BECs), highlighting their roles in immune cell activation and homeostasis. Potential strategies to restore aged LNSC function, such as enhancing LNSC activation during vaccination and using senotherapeutics, are explored. Outstanding questions regarding the mechanisms of LNSC ageing and how ageing of the LN stroma might impact autoimmune disorders are also addressed. This review aims to stimulate further research into the characterisation of aged LNSCs and the development of therapeutic interventions to improve immune function in the older adults.

References

Chen W, Lin I, Lee C, Chen Y . Aged Skeletal Muscle Retains the Ability to Remodel Extracellular Matrix for Degradation of Collagen Deposition after Muscle Injury. Int J Mol Sci. 2021; 22(4). PMC: 7924602. DOI: 10.3390/ijms22042123. View

Hadamitzky C, Spohr H, Debertin A, Guddat S, Tsokos M, Pabst R . Age-dependent histoarchitectural changes in human lymph nodes: an underestimated process with clinical relevance?. J Anat. 2010; 216(5):556-62. PMC: 2871991. DOI: 10.1111/j.1469-7580.2010.01213.x. View

Denton A, Dooley J, Cinti I, Silva-Cayetano A, Fra-Bido S, Innocentin S . Targeting TLR4 during vaccination boosts MAdCAM-1 lymphoid stromal cell activation and promotes the aged germinal center response. Sci Immunol. 2022; 7(71):eabk0018. PMC: 7612953. DOI: 10.1126/sciimmunol.abk0018. View

Mannick J, Del Giudice G, Lattanzi M, Valiante N, Praestgaard J, Huang B . mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014; 6(268):268ra179. DOI: 10.1126/scitranslmed.3009892. View

Takeuchi A, Ozawa M, Cui G, Ikuta K, Katakai T . Lymph Node Stromal Cells: Diverse Meshwork Structures Weave Functionally Subdivided Niches. Curr Top Microbiol Immunol. 2021; 434:103-121. DOI: 10.1007/978-3-030-86016-5_5. View

Abe Y, Sakata-Yanagimoto M, Fujisawa M, Miyoshi H, Suehara Y, Hattori K . A single-cell atlas of non-haematopoietic cells in human lymph nodes and lymphoma reveals a landscape of stromal remodelling. Nat Cell Biol. 2022; 24(4):565-578. PMC: 9033586. DOI: 10.1038/s41556-022-00866-3. View

Chen X, Luo Y, Zhu Q, Zhang J, Huang H, Kan Y . Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism. Nat Aging. 2024; 4(6):814-838. PMC: 11186790. DOI: 10.1038/s43587-024-00612-4. View

Amador-Patarroyo M, Rodriguez-Rodriguez A, Montoya-Ortiz G . How does age at onset influence the outcome of autoimmune diseases?. Autoimmune Dis. 2011; 2012:251730. PMC: 3238350. DOI: 10.1155/2012/251730. View

Gonzalez-Loyola A, Petrova T . Development and aging of the lymphatic vascular system. Adv Drug Deliv Rev. 2020; 169:63-78. DOI: 10.1016/j.addr.2020.12.005. View

10.

Morrisette-Thomas V, Cohen A, Fulop T, Riesco E, Legault V, Li Q . Inflamm-aging does not simply reflect increases in pro-inflammatory markers. Mech Ageing Dev. 2014; 139:49-57. PMC: 5881904. DOI: 10.1016/j.mad.2014.06.005. View

11.

Fletcher A, Lukacs-Kornek V, Reynoso E, Pinner S, Bellemare-Pelletier A, Curry M . Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J Exp Med. 2010; 207(4):689-97. PMC: 2856033. DOI: 10.1084/jem.20092642. View

12.

Nadafi R, Gago de Graca C, Keuning E, Koning J, de Kivit S, Konijn T . Lymph Node Stromal Cells Generate Antigen-Specific Regulatory T Cells and Control Autoreactive T and B Cell Responses. Cell Rep. 2020; 30(12):4110-4123.e4. DOI: 10.1016/j.celrep.2020.03.007. View

13.

Park J, Shin D . Senotherapeutics and Their Molecular Mechanism for Improving Aging. Biomol Ther (Seoul). 2022; 30(6):490-500. PMC: 9622307. DOI: 10.4062/biomolther.2022.114. View

14.

Pulendran B, Arunachalam P, OHagan D . Emerging concepts in the science of vaccine adjuvants. Nat Rev Drug Discov. 2021; 20(6):454-475. PMC: 8023785. DOI: 10.1038/s41573-021-00163-y. View

15.

Lananna B, Imai S . Friends and foes: Extracellular vesicles in aging and rejuvenation. FASEB Bioadv. 2021; 3(10):787-801. PMC: 8493967. DOI: 10.1096/fba.2021-00077. View

16.

Simon T, Li L, Wagner C, Zhang T, Saxena V, Brinkman C . Differential Regulation of T-cell Immunity and Tolerance by Stromal Laminin Expressed in the Lymph Node. Transplantation. 2019; 103(10):2075-2089. PMC: 6768765. DOI: 10.1097/TP.0000000000002774. View

17.

Bell M, Kutzler M . An old problem with new solutions: Strategies to improve vaccine efficacy in the elderly. Adv Drug Deliv Rev. 2022; 183:114175. DOI: 10.1016/j.addr.2022.114175. View

18.

Manni G, Buratta S, Pallotta M, Chiasserini D, Di Michele A, Emiliani C . Extracellular Vesicles in Aging: An Emerging Hallmark?. Cells. 2023; 12(4). PMC: 9954704. DOI: 10.3390/cells12040527. View

19.

Silva-Cayetano A, Fra-Bido S, Robert P, Innocentin S, Burton A, Watson E . Spatial dysregulation of T follicular helper cells impairs vaccine responses in aging. Nat Immunol. 2023; 24(7):1124-1137. PMC: 10307630. DOI: 10.1038/s41590-023-01519-9. View

20.

Astarita J, Cremasco V, Fu J, Darnell M, Peck J, Nieves-Bonilla J . The CLEC-2-podoplanin axis controls the contractility of fibroblastic reticular cells and lymph node microarchitecture. Nat Immunol. 2014; 16(1):75-84. PMC: 4270928. DOI: 10.1038/ni.3035. View