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 4

PREX1 facilitates effector T cell differentiation.

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PREX1 facilitates effector T cell differentiation. Naive CD4+ T cells we...
Naive CD4+ T cells were activated with anti-CD3/anti-CD28 antibody–coated polystyrene beads. (A) RAC1-GTP was measured at indicated times of activation. (B) RAC1-GTP was measured at 5 minutes of activation in control- or PREX1 siRNA–transfected cells from 4 older adults. Statistical analysis was done by 1-tailed, paired Student’s t test. *P < 0.05. (C) RAC1-GTP was measured after 5 minutes of activation in naive CD4+ T cells from 7 young and 7 older adults. Statistical analysis was done by 2-tailed, unpaired Student’s t test. **P < 0.01. (D) Naive CD4+ T cells from 6 older adults were activated for 5 days after control or PREX1 silencing. BLIMP1 and TCF1 expression was measured by flow cytometry. Statistical analysis was done by 2-tailed, paired Student’s t test. **P < 0.01. (E) Schematics of in vivo studies. OT-II naive CD4+ T cells transduced with shCtrl or shPREX1 were injected into B6 mice. Eight days after injection, spleens were harvested and CD4+ T cells were enriched and stained for indicated markers. (F) Frequencies of GFP+CD4+ T cells transduced with shCtrl (red) or shPREX1 (blue) expressing indicated markers (bottom). Five mice per group. (G) Ratio of CD44+CD62L– effector memory (EM) to CD44+CD62L+ central memory (CM) T cells. Five mice per group. Statistical analysis of F and G was done by 2-tailed, unpaired Student’s t test. **P < 0.01.