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 3

PREX1 accelerates homeostatic proliferation of naive CD4+ T cells.

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PREX1 accelerates homeostatic proliferation of naive CD4+ T cells. Naive...
Naive CD4+ T cells from older adults were transfected with control or PREX1 siRNA, incubated with IL-7 (5 ng/mL) for 14–20 days, and assayed for (A) apoptosis (n = 3), (B) CellTrace Violet (CTV) dilution (n = 4), and (C) Ki-67 expression (n = 6). Statistical analysis was done by 2-tailed, paired Student’s t test. *P < 0.05, **P < 0.01. (D) Ki-67 expression in naive CD4+ T cells directly ex vivo from 12 young and 10 older adults. Statistical analysis was done by 2-tailed, unpaired Student’s t test. *P < 0.05. (E) Schematics of in vivo studies. Human naive CD4+ T cells from 8 older adults, transfected with siCtrl or siPREX1, were injected into NSG mice. One week after injection, spleens were harvested. (F and G) Frequencies of (F) apoptotic (n = 8) and (G) Ki-67–expressing (n = 8) human CD4+ T cells were determined. Statistical analysis was done by 2-tailed, paired Student’s t test. *P < 0.05. (H) Mouse CD4+ T cells were transfected with either control or mouse Prex1 siRNA and assayed for PREX1 expression. (I) Schematics of in vivo studies. CD45.1+CD4+ T cells transfected with siCtrl or siPREX1 were stained with CFSE or CTV and injected into irradiated B6 CD45.2 mice. One week after injection, spleens were harvested. (J–L) Frequencies of (J) divided cells (n = 7), (K) Ki-67–expressing CD4+ T cells (n = 7), and (L) CD62L-expressing CD4+ T cells (n = 7). Statistical analysis was done by 2-tailed, paired Student’s t test. **P < 0.01, ***P < 0.001.