PREX1 improves homeostatic proliferation to maintain a naive CD4+ T cell compartment in older age
Huimin Zhang, Hirohisa Okuyama, Abhinav Jain, Rohit R. Jadhav, Bowen Wu, Ines Sturmlechner, Jose Morales, Shozo Ohtsuki, Cornelia M. Weyand, Jӧrg J. Goronzy
Huimin Zhang, Hirohisa Okuyama, Abhinav Jain, Rohit R. Jadhav, Bowen Wu, Ines Sturmlechner, Jose Morales, Shozo Ohtsuki, Cornelia M. Weyand, Jӧrg J. Goronzy
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Research Article Aging Immunology

PREX1 improves homeostatic proliferation to maintain a naive CD4+ T cell compartment in older age

Abstract

The human adult immune system maintains normal T cell counts and compensates for T cell loss throughout life, mainly through peripheral homeostatic proliferation after the ability of the thymus to generate new T cells has rapidly declined at adolescence. This process is mainly driven by STAT5-activating cytokines, most importantly IL-7, and is very effective in maintaining a large naive CD4+ T cell compartment into older age. Here, we describe that naive CD4+ T cells undergo adaptations to optimize IL-7 responses by upregulating the guanine-nucleotide exchange factor PREX1 in older age. PREX1 promotes nuclear translocation of phosphorylated STAT5, thereby supporting homeostatic proliferation in response to IL-7. Through the same mechanism, increased expression of PREX1 also biases naive cells to differentiate into effector T cells. These findings are consistent with the concept that primarily beneficial adaptations during aging, i.e., improved homeostasis, account for unfavorable functions of the aged immune system, in this case biased differentiation.

Authors

Huimin Zhang, Hirohisa Okuyama, Abhinav Jain, Rohit R. Jadhav, Bowen Wu, Ines Sturmlechner, Jose Morales, Shozo Ohtsuki, Cornelia M. Weyand, Jӧrg J. Goronzy

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Figure 1

Naive CD4+ T cells from older adults have a quiescence exit gene signature.

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Naive CD4+ T cells from older adults have a quiescence exit gene signatu...
(A) UMAPs generated from scATAC-seq data, scRNA-seq data, and combined data sets of peripheral naive CD4+ T cells from 2 young individuals (cyan) and 2 older individuals (magenta). (B) Ranking of ChromVar transcription factor (TF) deviation scores from scATAC-seq data. TFs ranking at the top are indicated. (C) TF deviation scores projected on UMAP space of integrated scRNA-seq/scATAC-seq data. (D) Quiescence-associated pathways or gene scores were projected onto integrated UMAPs. Pathway definition followed the gene grouping criteria described in Cheung and Rando (25). (E) Volcano plot of gene scores from scATAC-seq data comparing cells from young and older adults. Cyan color indicates genes with more accessible regulatory sites in cells from young adults and magenta in those from older adults. Bolded circles highlight some of the top differential genes. (F) Gene score of indicated genes projected on the integrated UMAP space. (G) Genome tracks of the PREX1 promoter region. Magenta shades highlight those peaks more open in older adults. (H) PREX1 transcript levels from bulk RNA-seq. RPKM, reads per kilobase per million mapped reads. Data presented as mean ± SEM. Significance was assessed by 2-tailed, paired Student’s t test. (I) PREX1 immunoblot of naive CD4+ T cells from 5 young and 5 older adults (upper panel). Summary of PREX1 protein expression in naive CD4+ T cells from 10 young and 10 older adults (bottom panel). Data presented as mean ± SEM. Significance was assessed by 2-tailed, unpaired Student’s t test. **P < 0.01.