mTOR signaling promotes a robust and continuous production of IFN‐γ by human memory CD8⁺ T cells and their proliferation

Abstract

Human CD8 + T cells are functionally heterogeneous and can be divided into phenotypically and functionally distinct subsets according to CCR7 and CD45RA expression levels. Among these, CCR7 low CD45RA low effector memory CD8 + T cells (Tem) and CCR7 low CD45RA high CD8 + T cells, which are designated as Temra and considered to be terminally differentiated cells, are Ag-experienced T cells but show different functionalities. Here, we show that, while Tem proliferate vigorously and produce IFN-γ persistently and robustly, Temra proliferate poorly and lose the ability to produce IFN-γ over time after TCR stimulation. Temra showed impaired cell growth upon TCR stimulation, which was associated with defective activation of the mammalian target of rapamycin (mTOR) signaling. Furthermore, rapamycin, an inhibitor of mTOR signaling, interfered with the robust and continuous proliferation of and IFN-γ production by Tem at later time points after TCR stimulation. Thus, these data collectively indicate that activation of mTOR signaling is required for the robust functions of Tem cells in humans and suggest that defective mTOR signaling in Temra contributes to their functional impairment.Keywords: CCR7 r CD45RA r CD8 + T cells r IFN-γ r mTOR signaling Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMemory CD8 + T cells develop and persist for a long period of time after the first encounter with exogenous antigen [1,2]. They are phenotypically and functionally heterogeneous and surface markers have been used to delineate different memory T-cell subsets. For example, in mice, CD62L low CD127 low cells are called effector memory cells and CD62L high CD127 high cells are called central memory cells [3,4]. It has been proposed that effector memory cells display a higher ability to produce effector cytokines than central memory cells, whereas the latter display a higher ability to proliferate in response to secondary Ag encounter than the former, and that they are in anatomically different locations [4,5].Correspondence: Dr. Ruka Setoguchi e-mail: ruka@ak.med.kyoto-u.ac.jp Human CD8 + T cells in peripheral blood are also heterogeneous and can be divided into four subpopulations according to their level of surface expression of CCR7 and CD45RA, CCR7 high CD45RA high naïve phenotype, CCR7 high CD45RA low central memory (Tcm) phenotype, CCR7 low CD45RA low effector memory (Tem) phenotype, and CCR7 low CD45RA high CD8 + T cells that are considered to be terminally differentiated cells (Temra) [6,7] The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr kinase that plays an important role in promoting mRNA translation and protein synthesis [16,17]. One of the key players operating downstream of mTOR signaling is ribosomal protein S6 kinase (S6K), and one of its major substrates, ribosomal protein S6 (rpS6), is essential for ribosomal biogenesis [18]. Activation of mTOR signaling in T cells occurs in response to nutrients, cytokines, an...

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“…TEMRA cells represent an EM subset associated with chronic Ag exposure and immune system aging that is characterized by a decreased proliferation potential and conserved strong effector activity (25,26). As indicated previously, EM and TEMRA cells were very similar at the epigenetic and gene-expression levels.…”

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“…However, the reports about the function of rapamycin on CD8 + T cells are controversial. Ruka et al indicated that rapamycin inhibited the IFN-γ production by CD8 + T cells (38). Bak et al showed that rapamycin treatment increased the frequency of antigen-specific CD8 + T cells and IFN-γ secretion (39).…”

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“…The mTOR-Akt pathway plays an important role in the formation of memory T cells. Accordingly, mTOR inhibitors (mTORi) permit the differentiation of naïve T cells into cells with a memory phenotype and allow the production of IL-2 (Setoguchi et al, 2015 ; Merino et al, 2016 ). However, IL-2 production driven by mTORi also allows the differentiation of naïve T cells into Treg cells (Battaglia et al, 2005 ; Kopf et al, 2007 ; Wang et al, 2012 ).…”

“…In contrast, rapamycin was able to control the proliferation of memory T cells only at a high concentration (Merino et al, 2016 ). The mTOR pathway is well-documented to promote continuous production of IFN-γ by memory T cells (Setoguchi et al, 2015 ). However, rapamycin fails to control IFN-γ production by memory T cells (Merino et al, 2016 ).…”