TY - JOUR
T1 - Early age-related atrophy of cutaneous lymph nodes precipitates an early functional decline in skin immunity in mice with aging
AU - Sonar, Sandip Ashok
AU - Uhrlaub, Jennifer L.
AU - Coplen, Christopher P.
AU - Sempowski, Gregory D.
AU - Dudakov, Jarrod A.
AU - Van den Brink, Marcel R.M.
AU - LaFleur, Bonnie J.
AU - Jergovic, Mladen
AU - Nikolich-Zugich, Janko
N1 - Funding Information:
Competing interest statement: J.N.-Z.≤ is co-chair of the scientific advisory board of and receives research funding from Young Blood Institute (YBI), Inc. YBI, Inc. had no influence on any aspect of this work or the present manuscript. This article is a PNAS Direct Submission.
Funding Information:
ACKNOWLEDGMENTS. We thank Dr. Y. Zhuang (Duke University) for generously providing us TCRδCre.ER mice. We thank Mr. Jose L. Padilla-Torres, and the university animal care facility, (University of Arizona, Tucson, AZ) for maintaining mouse colonies. We are grateful to the University of Arizona/University of Arizona Cancer Center (UACC) Shared Flow Cytometry Resource and the Imaging Core Facility, supported by the UACC Support Grant P30 CA023074 for technical help with flow cytometry and microscopy. We thank Dr. Laura Hale (the Duke Human Vaccine Institute, Duke University, Durham, NC); Dr. Nancy R. Manley (Department of Genetics, University of Georgia, Athens, GA); Dr. Ellen R. Richie (MD Anderson Cancer Center, Austin, TX); and Dr. Lauren I. R. Ehrlich (Department of Molecular Biosciences, Institute of Cellular and Molecular Biology, University of Texas at Austin, Austin, TX) for scientific discussion, critical reading of manuscript, and other input. This work is supported in part by US Public Health Service Awards AG052359 and AG020719 and the Bowman Endowed Professorship in Medical Sciences (J.N.-≤Z.). Work performed at Duke University was in the Duke Regional Biocontainment Laboratory, which received partial support for construction from NIH/National Institute of Allergy and Infectious Diseases (AI058607 to G.D.S.).
Publisher Copyright:
© 2022 National Academy of Sciences. All rights reserved.
PY - 2022/4/26
Y1 - 2022/4/26
N2 - Secondary lymphoid organs (SLOs) (including the spleen and lymph nodes [LNs]) are critical both for the maintenance of naive T (TN) lymphocytes and for the initiation and coordination of immune responses. How they age, including the exact timing, extent, physiological relevance, and the nature of age-related changes, remains incompletely understood. We used "time stamping" to indelibly mark newly generated naive T cells (also known as recent thymic emigrants) (RTEs) in mice, and followed their presence, phenotype, and retention in SLOs. We found that SLOs involute asynchronously. Skin-draining LNs atrophied by 6 to 9 mo in life, whereas deeper tissuedraining LNs atrophied by 18 to 20 mo, as measured by the loss of both TN numbers and the fibroblastic reticular cell (FRC) network. Time-stamped RTEs at all ages entered SLOs and successfully completed postthymic differentiation, but the capacity of older SLOs to maintain TN numbers was reduced with aging, and that trait did not depend on the age of TNs. However, in SLOs of older mice, these cells exhibited an emigration phenotype (CCR7loS1P1hi), which correlated with an increase of the cells of the same phenotype in the blood. Finally, upon intradermal immunization, RTEs generated in mice barely participated in de novo immune responses and failed to produce well-armed effector cells detectable in blood as early as by 7 to 8 mo of age. These results highlight changes in structure and function of superficial secondary lymphoid organs in laboratory mice that are earlier than expected and are consistent with the long-appreciated reduction of cutaneous immunity with aging.
AB - Secondary lymphoid organs (SLOs) (including the spleen and lymph nodes [LNs]) are critical both for the maintenance of naive T (TN) lymphocytes and for the initiation and coordination of immune responses. How they age, including the exact timing, extent, physiological relevance, and the nature of age-related changes, remains incompletely understood. We used "time stamping" to indelibly mark newly generated naive T cells (also known as recent thymic emigrants) (RTEs) in mice, and followed their presence, phenotype, and retention in SLOs. We found that SLOs involute asynchronously. Skin-draining LNs atrophied by 6 to 9 mo in life, whereas deeper tissuedraining LNs atrophied by 18 to 20 mo, as measured by the loss of both TN numbers and the fibroblastic reticular cell (FRC) network. Time-stamped RTEs at all ages entered SLOs and successfully completed postthymic differentiation, but the capacity of older SLOs to maintain TN numbers was reduced with aging, and that trait did not depend on the age of TNs. However, in SLOs of older mice, these cells exhibited an emigration phenotype (CCR7loS1P1hi), which correlated with an increase of the cells of the same phenotype in the blood. Finally, upon intradermal immunization, RTEs generated in mice barely participated in de novo immune responses and failed to produce well-armed effector cells detectable in blood as early as by 7 to 8 mo of age. These results highlight changes in structure and function of superficial secondary lymphoid organs in laboratory mice that are earlier than expected and are consistent with the long-appreciated reduction of cutaneous immunity with aging.
KW - T cells
KW - aging
KW - homeostasis
KW - secondary lymphoid organs
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U2 - 10.1073/pnas.2121028119
DO - 10.1073/pnas.2121028119
M3 - Article
C2 - 35439062
AN - SCOPUS:85128792529
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 17
M1 - e2121028119
ER -