Abstract
Cellular proliferation in response to mitogenic stimuli is negatively regulated by the Cip/Kip and the Ink4 families of cyclin-dependent kinase (CDK) inhibitors. Several of these proteins are elevated in anergic T cells, suggesting a potential role in the induction or maintenance of tolerance. Our previous studies showed that p27kip1 is required for the induction of T cell anergy and transplantation tolerance by costimulatory blockade, but a role for Ink4 proteins in these processes has not been established. Here we show that CD4+ T cells from mice genetically deficient for p18ink4c divide more rapidly than wild-type cells in response to antigenic, costimulatory and growth factor signals. However, this gain of proliferative function was accompanied by a moderate increase in the rate of cell death, and was accompanied by an overall defect in the generation of alloreactive IFNγ-producing effector cells. Consistent with this, p18ink4c-deficient T cells were unable to induce graft-vs-host disease in vivo, and p18ink4c deficiency cooperated with costimulatory blockade to significantly increase the survival of fully mismatched allografts in a cardiac transplantation model. While both p18ink4c and p27kip1 act to restrict T cell proliferation, p18ink4c exerts an opposite effect from p27kip1 on alloimmunity and organ transplant rejection, most likely by sustaining T cell survival and the development of effector function. Our studies point to additional important links between the cell cycle machinery and the processes of T cell differentiation, survival and tolerance.
Highlights
Cyclin-dependent kinase inhibitors negatively regulate the cell cycle, helping to set the threshold for cell cycle entry and promoting exit from cell cycle in response to growth factor withdrawal, inhibitory cytokines, contact inhibition, DNA damage, and senescence
Blockade of CD28 costimulation resulted in nearly complete cessation of DNA synthesis and mitosis at later time points (Fig. 1 A, B and C, second row), and by the end of the response lead to a 5-fold decrease in cumulative cell division by WT CD4+ T cells (Fig. 1 C, second row). p18ink4c-deficient CD4+ T cells exhibited only a 40% reduction in DNA synthesis at 36 hours in response to costimulatory blockade (Fig. 1 A and B, second row), which represented only a 10% reduction compared to WT cells receiving physiologic costimulation
We found that CD4+ T cells lacking p18ink4c responded to the addition of exogenous IL-2 with augmented early DNA synthesis compared to WT cells (Fig. 1 A and B, bottom row), as well as increased cumulative cell division at day 3 (Fig. 1 C, bottom row)
Summary
Cyclin-dependent kinase inhibitors negatively regulate the cell cycle, helping to set the threshold for cell cycle entry and promoting exit from cell cycle in response to growth factor withdrawal, inhibitory cytokines, contact inhibition, DNA damage, and senescence. The enlarged lymphoid compartments of p18ink4c- and p27kip1-deficient mice are due to increased generation of naıve T cells, as spontaneous accumulation of activated T lymphocytes in the periphery is not observed. P27kip is an established, intracellular sensor of costimulatory and growth factor signals in both CD4+ and CD8+ T cells [8,9,10,11,12,13,14], where it limits clonal expansion. We have utilized p18ink4c2/2 mice to determine whether p18ink4c affects the threshold for costimulatory and growth factor receptor signaling in T cells, and to determine the role of p18ink4c in the induction of anergy and tolerance. T cells lacking p18ink4c failed to induce graft-vs.-host disease (GVHD) in fully MHC-mismatched recipients, and costimulatory blockade was much more effective at preventing cardiac allograft rejection in recipient mice lacking p18ink4c
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