Abstract
Aging is associated with a massive infiltration of T lymphocytes in the lacrimal gland. Here, we aimed to characterize the immune phenotype of aged CD4+ T cells in this tissue as compared with lymphoid organs. To perform this, we sorted regulatory T cells (Tregs, CD4+CD25+GITR+) and non-Tregs (CD4+CD25negGITRneg) in lymphoid organs from female C57BL/6J mice and subjected these cells to an immunology NanoString® panel. These results were confirmed by flow cytometry, live imaging, and tissue immunostaining in the lacrimal gland. Importantly, effector T helper 1 (Th1) genes were highly upregulated on aged Tregs, including the master regulator Tbx21. Among the non-Tregs, we also found a significant increase in the levels of EOMESmed/high, TbetnegIFN-γ+, and CD62L+CD44negCD4+ T cells with aging, which are associated with cell exhaustion, immunopathology, and the generation of tertiary lymphoid tissue. At the functional level, aged Tregs from lymphoid organs are less able to decrease proliferation and IFN-γ production of T responders at any age. More importantly, human lacrimal glands (age range 55–81 years) also showed the presence of CD4+Foxp3+ cells. Further studies are needed to propose potential molecular targets to avoid immune-mediated lacrimal gland dysfunction with aging.
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Data availability
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author. The datasets for this study can be found in the GEO repository (Access ID GSE192408).
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Acknowledgements
We gratefully acknowledge Dr. Ron Korstanje, Hannah Donnato, and Laura Robinson from the Nathan Shock Center for Excellence of Aging at Jackson Laboratory for their contribution and Dr. Will Schott at the Flow Cytometry Service at the Jackson Laboratory for the expert assistance with the work described in this publication. We also acknowledge the expert assistance of Brandon Saxton and Joel Sederstrom with the imaging cytometer at Baylor College of Medicine. Leiqi Zhang is acknowledged with the aged colony management. The authors would like to thank Hong Nguyen for the excellent technical assistance (Institute of Functional and Clinical Anatomy, Friedrich-Alexander-Universität Erlangen-Nürnberg). Moreover, the authors sincerely thank those who donated their bodies to science so that anatomical research could be performed.
Funding
This work was supported by NIH EY030447 (CSdeP), NEI Training Grant in Vision Sciences T32 EY007001 (HH), NIH/NEI EY002520 (Core Grant for Vision Research Department of Ophthalmology), NIH Pathology Core (P30CA125123), BCM Genomic & RNA Profiling Core GARP Core (P30 Digestive Disease Center Support Grant [NIDDK-DK56338]), and Baylor Cytometry and Cell Sorting Core (CPRIT Core Facility Support Award [CPRIT-RP180672], P30 Cancer Center Support Grant [NCI-CA125123], NIH-RR024574, and NIH S10 OD025251 [Union BioMetrica BioSorter]). Further research support was provided by the NIH to the Jackson Laboratory Nathan Shock Center of Excellence in the Basic Biology of Aging (AG038070) Pilot Grant (CSdeP), Research to Prevent Blindness (unrestricted grant to the Department of Ophthalmology), the Hamill Foundation, and the Sid Richardson Foundation and ARVO Roche Collaborative Research Fellowship (JGG). Claudia M. Trujillo-Vargas received supplemental salary support from Facultad de Medicina, Universidad de Antioquia, UdeA, Medellin, Colombia. This work was supported by the Deutsche Forschungsgemeinschaft (DFG) grant PA738/15–1 to FP.
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CSdeP and CMT-V were involved in the conception and design of the study. CSdeP, CMT-V, KEM, HH, RGdeS, ZY, JD, and FP were involved in data acquisition. CSdeP, CMT-V, KEM, JGG, JD, and FP were involved in the data analysis and interpretation. CMT-V drafted the manuscript, and CSdeP edited it. All authors contributed to the article and approved the submitted version.
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Trujillo-Vargas, C.M., Mauk, K.E., Hernandez, H. et al. Immune phenotype of the CD4+ T cells in the aged lymphoid organs and lacrimal glands. GeroScience 44, 2105–2128 (2022). https://doi.org/10.1007/s11357-022-00529-z
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DOI: https://doi.org/10.1007/s11357-022-00529-z