Inhibition of Cell Cycle Progression by Rapamycin Induces T Cell Clonal Anergy Even in the Presence of Costimulation

Abstract

Costimulation (signal 2) has been proposed to inhibit the induction of T cell clonal anergy by either directly antagonizing negative signals arising from TCR engagement (signal 1) or by synergizing with signal 1 to produce IL-2, which in turn leads to proliferation and dilution of negative regulatory factors. To better define the cellular events that lead to the induction of anergy, we used the immunosuppressive agent rapamycin, which blocks T cell proliferation in late G1 phase but does not affect costimulation-dependent IL-2 production. Our data demonstrate that full T cell activation (signal 1 plus 2) in the presence of rapamycin results in profound T cell anergy, despite the fact that these cells produce copious amounts of IL-2. Similar to conventional anergy (induction by signal 1 alone), the rapamycin-induced anergic cells show a decrease in mitogen-activated protein kinase activation, and these cells can be rescued by culture in IL-2. Interestingly, the rapamycin-induced anergic cells display a more profound block in IL-3 and IFN-γ production upon rechallenge. Finally, in contrast to rapamycin, full T cell activation in the presence of hydroxyurea (which inhibits the cell cycle in early S phase) did not result in anergy. These data suggest that it is neither the direct effect of costimulation nor the subsequent T cell proliferation that prevents anergy induction, but rather the biochemical events that occur upon progression through the cell cycle from G1 into S phase.

Vitamin A-treated natural killer cells reduce interferon-gamma production and support regulatory T cell differentiation

“…First, our results show that NK cells exposed to atRA were unable to efficiently engage mTORC1 and increase cMyc expression in response to IL-18. mTORC1 and cMyc are metabolic regulators that increase glycolysis rate and support pro-inflammatory effector responses in T cells (Powell, Lerner, & Schwartz, 1999; R. Wang et al, 2011; Zheng et al, 2007). NK cells require mTORC1 for development, as well as for the IL-15-induced IFN-γ production by elevating glycolytic rate (Marcais et al, 2014).…”

Kruppel-like factor 1–GATA1 fusion protein improves the sickle cell disease phenotype in mice both in vitro and in vivo

“… 77 , 78 This donor-derived hematopoiesis has been shown sufficient to reverse the SCD phenotype. 77 , 78 , 79 A low level of irradiation, together with rapamycin use, has been shown to suppress the immune response and prevent the occurrence of graft-versus-host disease. 79 , 80 In our SCD mouse transplantation studies, we achieved 36% ± 6% engraftment of donor cells in the bone marrow (data not shown), which is consistent with results in a recent report.…”

“… 77 , 78 , 79 A low level of irradiation, together with rapamycin use, has been shown to suppress the immune response and prevent the occurrence of graft-versus-host disease. 79 , 80 In our SCD mouse transplantation studies, we achieved 36% ± 6% engraftment of donor cells in the bone marrow (data not shown), which is consistent with results in a recent report. 81 Because cytokine pretreatment could induce HSC differentiation and loss of long-term repopulating activity, 82 in our protocol, mouse HSCs were directly incubated with lentivirus without cytokine prestimulation before gene transduction.…”

Pathogenesis and treatment of Sjogren’s syndrome: Review and update

“…mTOR likely prevents anergy induction by IL-2 expression in T cells. A previous study found that by blocking mTOR with rapamycin, the cell cycle of clonal T cells was inhibited, while it induced cell anergy even with costimulations ( 101 ). In the process of naïve T cell differentiation, mTOR mediates the transformation to Th17 or Treg cells by altering the sensitivity of T cells to TGF-β, which influences the effects of STAT3 signaling ( 102 ).…”