Quantitative restoration of immune defense in old animals determined by naive antigen-specific CD8 T-cell numbers

Jennifer L Uhrlaub; Mladen Jergović; Christine M Bradshaw; Sandip Sonar; Christopher P Coplen; Jarrod Dudakov; Kristy O Murray; Marion C Lanteri; Michael P Busch; Marcel R M van den Brink; Janko Nikolich-Žugich

doi:10.1111/acel.13582

Quantitative restoration of immune defense in old animals determined by naive antigen-specific CD8 T-cell numbers

Aging Cell. 2022 Apr;21(4):e13582. doi: 10.1111/acel.13582. Epub 2022 Mar 15.

Authors

Jennifer L Uhrlaub^{1

2}, Mladen Jergović^{1

2}, Christine M Bradshaw^{1

2}, Sandip Sonar^{1

2}, Christopher P Coplen^{1

2}, Jarrod Dudakov^{3

4}, Kristy O Murray^{5

6}, Marion C Lanteri⁷, Michael P Busch⁷, Marcel R M van den Brink⁸, Janko Nikolich-Žugich^{1

2}

Affiliations

¹ Department of Immunobiology, University of Arizona College of Medicine, Tucson, Arizona, USA.
² University of Arizona, Center on Aging, University of Arizona, College of Medicine, Tucson, Tucson, Arizona, USA.
³ Program in Immunology, Clinical Research Division, and Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
⁴ Department of Immunology, University of Washington, Seattle, Washington, USA.
⁵ Department of Pediatrics, Section of Pediatric Tropical Medicine and National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, USA.
⁶ William T. Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, Texas, USA.
⁷ Blood Systems Research Institute, Vitalant Research Institute, San Francisco, California, USA.
⁸ Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York City, USA.

Abstract

Older humans and animals often exhibit reduced immune responses to infection and vaccination, and this often directly correlates to the numbers and frequency of naive T (Tn) cells. We found such a correlation between reduced numbers of blood CD8+ Tn cells and severe clinical outcomes of West Nile virus (WNV) in both humans naturally exposed to, and mice experimentally infected with, WNV. To examine possible causality, we sought to increase the number of CD8 Tn cells by treating C57BL/6 mice with IL-7 complexes (IL-7C, anti-IL-7 mAb bound to IL-7), shown previously to efficiently increase peripheral T-cell numbers by homeostatic proliferation. T cells underwent robust expansion following IL-7C administration to old mice increasing the number of total T cells (>fourfold) and NS4b:H-2D^b -restricted antigen-specific CD8 T cells (twofold). This improved the numbers of NS4b-specific CD8 T cells detected at the peak of the response against WNV, but not survival of WNV challenge. IL-7C-treated old animals also showed no improvement in WNV-specific effector immunity (neutralizing antibody and in vivo T-cell cytotoxicity). To test quantitative limits to which CD8 Tn cell restoration could improve protective immunity, we transferred graded doses of Ag-specific precursors into old mice and showed that injection of 5400 (but not of 1800 or 600) adult naive WNV-specific CD8 T cells significantly increased survival after WNV. These results set quantitative limits to the level of Tn reconstitution necessary to improve immune defense in older organisms and are discussed in light of targets of immune reconstitution.

Keywords: IL-7/ CD8 T cells; immune aging; immune rejuvenation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes
Cell Count
Interleukin-7
Mice
Mice, Inbred C57BL
West Nile Fever*
West Nile virus*

Substances

Interleukin-7

Abstract

Publication types

MeSH terms

Substances

Grants and funding