Novel mediators of human naive CD4 T cell resilience across the aging spectrum 3351

The Journal of Immunology 2025

Nelson M. Mukuka, Claire E. Gustafson, Kathy E. Henderson, Troy R. Torgerson, Garrett Strawn, Qiuyu Gong, M. Wharton, P. Skene et al.

Abstract

Abstract Description In humans, the loss of naive CD8 T cells is a hallmark of immune aging, whereas naive CD4 T cells are more resilient to this age-related decline. Maintenance of these naive T cell pools becomes crucially important for ongoing immune protection. The compartment-specific mechanism for this resilience is unknown. To identify specific factors that may mediate longevity in human naive CD4 T cells, we first used scRNA-seq to compare the numbers and transcriptional profiles of naive CD4 and CD8 T cell subsets from over 300 healthy adults across age. We observed that while core naive CD8 T cells decline with age, core naive CD4 T cells remain stable. Moreover, we observed significant age-related changes in the transcriptional profiles of naive T cells, with CD4 T cells showing significantly higher differential genes than CD8 T cells. While we detected several common differentially expressed transcription factors, naive CD4 T cells exhibited altered expression of TSHZ2, a known tumor suppressor, with age. We next developed protocols to knock-down or overexpress age-related transcription factors in primary naive CD4 T cells or naive CD4-like cell lines, respectively. Preliminary data show elevated TSHZ2 expression is associated with decreased T cell proliferation and collectively suggests that TSHZ2 may regulate cell cycle and impact naive CD4 T cell longevity in the context of healthy human aging. Funding Sources Research reported in this publication was supported by National Institute on Aging award K01AG068373 (to C.E.G.) and by the Allen Institute for Immunology. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

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