Abstract
Myeloid cell leukemia sequence-1 (Mcl-1) is a critical anti-apoptotic factor in T lymphocytes. However, in spite of the many pro-apoptotic proteins with proposed binding to Mcl-1, the specific interactions by which Mcl-1 regulates primary T-cell survival under different conditions have not been fully explored. Further, how different trophic cytokines modulate the specific role(s) of Mcl-1 is unknown. Here, we use genetic mouse models to dissect the roles of Mcl-1 in primary T lymphocytes. Using the inducible Mcl-1-floxed estrogen receptor-Cre fusion protein (Mcl-1f/fERCre) deletion system in combination with genetic modification of other B-cell lymphoma 2 (Bcl-2) family members, we show that loss of pro-apoptotic Bcl-2 homologous antagonist/killer (Bak) rescues the survival of Mcl-1-deficient T cells in the presence of IL-7. Without IL-7, the survival of Mcl-1-deficient cells cannot be rescued by loss of Bak, but is partially rescued by overexpression of Bcl-2 or loss of Bcl-2-interacting mediator of cell death (Bim). Thus, Mcl-1 and Bcl-2 have a shared role, the inhibition of Bim, in promoting T-cell survival during cytokine withdrawal. Finally, we show that other common gamma-chain (γc) cytokines differentially modulate the roles of Mcl-1. IL-15 has effects similar to those of IL-7 in memory T cells and naïve CD8+ cells, but not naïve CD4+ cells. However, IL-4 maintains Mcl-1 and Bcl-2 but also upregulates Bim and Bcl-2-associated X protein (Bax), thus altering the cell's dependence on Mcl-1.
Highlights
IL-7 and other cytokines, namely IL-2, IL-15, IL-4, IL-9, and IL-21, constitute a family that shares the gc-receptor subunit
We examine the survival of myeloid cell leukemia sequence-1 (Mcl-1)-deficient cells on BakÀ/À, BaxÀ/À, BimÀ/À, and B-cell lymphoma-2 (Bcl-2)-overexpressing backgrounds in the presence and absence of IL-7 and other gc-sharing cytokines
We previously showed that 4OHT-treated T cells from Mcl-1-floxed, ERCre-expressing (Mcl-1f/fERCre) mice died under different ex vivo conditions.[18]
Summary
IL-7 and other cytokines, namely IL-2, IL-15, IL-4, IL-9, and IL-21, constitute a family that shares the gc-receptor subunit. Each cytokine has a distinct biological role, several of them, IL-7 and IL-15, promote T-cell survival.[2] Studies from mice, primary cells, and cell lines have implicated the B-cell lymphoma-2 (Bcl-2) family, the Bcl-2/Bcl-2-interacting mediator of cell death (Bim)/Bcl-2associated X protein (Bax) axis, downstream of cytokine signaling,[3] but the role of myeloid cell leukemia sequence-1 (Mcl-1) in cytokine-induced survival is less well described. Pro-apoptotic Bcl-2 homologous antagonist/killer (Bak) and Bax self-oligomerize to form pores in mitochondrial membranes, and are required for the intrinsic pathway of apoptosis.[4,5] Pro-apoptotic BH3only proteins, such as Bim, Bid, Bad, Noxa, and Puma, are upstream initiators. We examine the survival of Mcl-1-deficient cells on BakÀ/À, BaxÀ/À, BimÀ/À, and Bcl-2-overexpressing backgrounds in the presence and absence of IL-7 and other gc-sharing cytokines. The data highlight the complex pathways that regulate primary T-cell survival, the role of Mcl-1, and the functions of gc cytokines
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
