Mice that lack IL-15 or the IL-15R α-chain (IL-15Rα) are deficient in peripheral CD8+, but not in CD4+, T cells. This CD8+ T cell-specific deficiency has now been investigated further by characterization of a new strain of IL-15Rα−/− mice. The adult mutant mice exhibited a specific reduction in the percentage of CD8-single positive TCRhigh thymocytes. The expression of Bcl-2 was reduced in both CD8+ thymocytes and naive T cells of the mutant animals, and the susceptibility of these cells to death was increased. Memory CD8+ cells were profoundly deficient in IL-15Rα−/−mice, and the residual memory-like CD8+ cells contained a high percentage of dead cells and failed to up-regulate Bcl-2 expression compared with naive CD8+ cells. Moreover, exogenous IL-15 both up-regulated the level of Bcl-2 in and reduced the death rate of wild-type and mutant CD8+ T cells activated in vitro. These results indicate that IL-15 and IL-15Rα regulate the expression of Bcl-2 in CD8+ T cells at all developmental stages. The reduced Bcl-2 content in CD8+ cells might result in survival defect and contribute to the reduction of CD8+ cells in IL-15Rα−/−mice.
We previously demonstrated that IL-3 stimulates transcription of the antiapoptotic gene mcl-1 via two promoter elements designated as the SIE and CRE-2 sites. To further study the functional role of these two DNA elements, mutant mice with targeted mutations of both SIE and CRE-2 sites (SC mutants) were generated. Homozygous SC mutants manifested a markedly reduced level of Mcl-1 in thymus but not in other major organs such as spleen, liver, lung, or heart. Reduced expression of Mcl-1 in SC mutant thymus resulted in attenuated positive selection of double-positive thymocytes into both CD4 and CD8 lineages, a result likely due to reduced survival of SC mutant double-positive thymocytes that were supposed to be positively selected. In contrast, in the peripheral lymphoid organs, only CD8؉ but not CD4 ؉ T cells were significantly reduced in homozygous SC mutant mice, a result consistent with a more dramatic decrease both of Mcl-1 expression and cell viability in mutant CD8؉ compared with mutant CD4؉ T cells. Impaired T cell development and peripheral CD8 ؉ lymphopenia in homozygous SC mutant mice were both cell autonomous and could be rescued by enforced expression of human Mcl-1. Together, the promoter-knock-in mouse model generated in this study not only revealed a Mcl-1, a member of the Bcl-2 family protein, was originally identified in the ML-1 human myeloid leukemia cell line that underwent phorbol ester-induced differentiation (1). Mcl-1 is widely expressed in various tissues and cell lineages, and a great number of studies indicate that Mcl-1 plays an apical role in many cell survival and death pathways (2). Mcl-1 deficiency results in embryonic lethality at the peri-implantation stage (3). Conditional knock-out approaches have thus been used to assess Mcl-1 functions in other tissues. Using this approach, Mcl-1 has been shown to be essential for the survival of many cell types in the hematopoietic system, including hematopoietic stem cells, lymphoid precursors, mature T and B lymphocytes, and neutrophils (4 -6).T cell progenitors arise from the bone marrow and migrate into the thymus to become early committed T cells that lack expression of TCR, CD4, and CD8. These cells are termed double-negative (DN) 3 thymocytes (7). DN thymocytes then develop in an ordered progression and mature into the CD4 ϩ CD8 ϩ double-positive (DP) stage (8). At this stage, immature DP thymocytes expressing unique TCRs are tested individually by two selection processes that eliminate cells whose TCRs either cannot recognize self peptide/MHC complex (positive selection) or react too strongly (negative selection). These two selection processes ensure that most DP thymocytes selected to differentiate into CD4 single-positive (SP) or CD8SP thymocytes, and eventually peripheral T cells, can respond properly when encountering foreign peptides in the context of self MHC in the periphery (8 -10). Many Bcl-2 family members have been shown to play a role in T cell development. Deletion of Bcl-2 resulted in rapid loss of thymocytes and naive...
In this study, we investigated the functional outcomes of CD4
Although IL-15 is known to be a T cell growth factor, the function in T cells of IL-15Rα, its high affinity receptor, remains unclear. We found that murine IL-15Rα−/− CD4+ T cells hyperproliferated in response to TCR stimulation, in vitro and in vivo, and displayed a lower TCR activation threshold than wild-type CD4+ T cells. TCR-induced activation of Zap70 and of the phospholipase C-γ1-NFATp, Ras-ERK-c-Fos, and Rac-JNK-c-Jun pathways was all augmented in IL-15Rα−/− CD4+ T cells. This in turn led to earlier IL-2Rα induction and higher IL-2 production, which most likely contribute to the hyperproliferation of IL-15Rα−/− CD4+ T cells. Exogenous IL-15 reduced levels of TCR-activated signals, transcription factors, IL-2, and IL-2Rα, and division in wild-type CD4+ T cells. These results reveal IL-15Rα to be a negative regulator for CD4+ T cell activation and demonstrate a novel layer of regulation of TCR signaling by a cytokine system.
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