Presentation: A Role of IL-15 in Maintaining IL-7Rαlow Memory CD8+ T Cells in Humans via Recovering the PI3K/AKT Pathway (2007)

140 A Role of IL-15 in Maintaining IL-7Rαlow Memory CD8+ T Cells in Humans via Recovering the PI3K/AKT Pathway

Purpose: Memory is a hallmark of T cell immunity that is involved in the development of autoimmune diseases such as lupus and rheumatoid arthritis (RA). Indeed, expansion of memory T cells including CD8+ T cells has been reported in these diseases. IL-7 is a key cytokine for memory T cell maintenance and the effect of IL-7 on T cells is dependent on the IL-7 receptor (R) α chain. Recently, we found two cell subsets expressing IL-7Rαhigh and low in CCR7- memory CD8+ T cells (CD45RA+/- CCR7-). IL-7Rαlow memory CD8+ T cells that produce effector cytokines and perforin have impaired proliferation and survival in response to T cell receptor (TCR) triggering and IL-7, respectively. These findings raise a question of how such cells are sustained, greater than 20% of peripheral CD8+ T cells in healthy humans, despite impaired IL-7- and TCR-mediated cell maintenance. IL-15, produced largely by dendritic cells, monocytes and stromal cells, can induce CD8+ T cell proliferation. Thus, we have investigated a potential role for IL-15 in maintaining IL-7Rαlow memory CD8+ T cells and its mechanism.
Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from healthy human subjects and stained with Abs to CD8, CCR7 and CD45RA as well as Abs to IL-7Rα, IL-15Rα, IL-2/-15Rβ, or isotype Abs. Cells were analyzed on an LSRII® flow cytometer. IL-7Rαhigh and low memory (CD45RA+/- CCR7-) CD8+ T cells were sorted from PBMCs using a FACSAria®. Expression of IL-15Ra, IL-2/-15Rb, eomesodermin and T-bet, transcriptional factors involved in IL-2/-15Rb expression, was measured in sorted cells using real-time PCR. Some sorted cells were stained with carboxyfluorescein diacetate (CFSE) and stimulated with PBS, IL-15, anti-CD3 Abs or a combination of the latter two in the presence or absence of chemicals inhibiting PI3K/AKT and ERK which are involved in the TCR signaling pathway. Also, phosphorylation of AKT was measured in sorted cells that were stimulated in the same conditions using Western blot.
Results: IL-7Rαlow memory CD8+ T cells express higher levels of IL-2/-15Rβ, a chain critical for IL-15 signaling, in association with increased expression of IL-2/-15Rb, eomesodermin and T-bet genes compared to IL-7Rαhigh memory CD8+ T cells. Plus, IL-7Rαlow memory CD8+ T cells proliferate in response to IL-15 alone and more significantly in response to a combination of IL-15 and anti-CD3 Abs via restoring impaired activation of PI3K/AKT pathway. Furthermore, such cell proliferation was inhibited by various PI3K/AKT inhibitors but not by ERK inhibitor PD98059.
Conclusions: Our findings indicate that IL-15 is involved in maintaining IL-7Rαlow memory CD8+ T cells in humans with and without TCR triggering via restoring activation of PI3K/AKT pathway. Also, our work suggests that targeting IL-15 and PI3K/AKT pathway could be considered to limit expansion of memory CD8+ T cells including IL-7Rαlow cells expressing perforin in autoimmune diseases with memory CD8+ T cell expansion.

 I. Kang, None.