Control of Effector CD8 ⁺ T Cell Function by the Transcription Factor Eomesodermin

Abstract

Activated CD8+ T cells play a critical role in host defense against viruses, intracellular microbes, and tumors. It is not clear if a key regulatory transcription factor unites the effector functions of CD8+ T cells. We now show that Eomesodermin (Eomes), a paralogue of T-bet, is induced in effector CD8+ T cells in vitro and in vivo. Ectopic expression of Eomes was sufficient to invoke attributes of effector CD8+ T cells, including interferon-gamma (IFN-gamma), perforin, and granzyme B. Loss-of-function analysis suggests Eomes may also be necessary for full effector differentiation of CD8+ T cells. We suggest that Eomesodermin is likely to complement the actions of T-bet and act as a key regulatory gene in the development of cell-mediated immunity.

Enforced Expression of Bcl-2 Partially Restores Cell Numbers but Not Functions of TCRγδ Intestinal Intraepithelial T Lymphocytes in IL-15-Deficient Mice

“…We found that enforced expression of Bcl-2 partially restored the number, but not functions of TCR␥␦ i-IEL in IL-15 KO mice. Furthermore, the recovered ␥␦ i-IEL developed in Bcl-2 Tg ϫ IL-15 KO mice expressed a reduced level of eomesdermin, transcription factor shown to be critical for effector function of NK and CD8 ϩ T cells (27,28). These results indicate nonredundant roles of IL-15 in the development of functional TCR␥␦ i-IEL.…”

“…It is notable that the TCR␥␦ i-IEL in Bcl-2 Tg ϫ IL-15 KO mice expressed a reduced level of T-box transcriptional factors, eomesodermin and T-bet. Eomesodermin is expressed by activated CD8 ϩ T cells and NK cells and regulates expressions of genes encoding IFN-␥ and cytolytic molecules (27,28). T-bet has a critical function in the differentiation and function of Th1 cells through regulating the expression of IFN-␥ and IL-12R␤2 (37,38).…”

Temporal Dissection of T-bet Functions

“…These results were confirmed by the generation of T-bet-deficient mice, which lack Th1 cells and instead exhibit an enlarged Th2 compartment (6). In addition to Th1 cells, T-bet is detected in several other immune cells, including CD8 ϩ T cells (3,5,6), dendritic cells (7), B cells (8), NK cells and NKT cells (9 -11). T-bet regulates expression of numerous immune systemassociated genes, including cytokines (4), cytokine receptors (9 -12), chemokines (7,11), chemokine receptors (4,11,13) and cytotoxicity (9,11).…”

“…This fusion protein resulted in a tamoxifen-regulated T-bet, T-bet-ER, which could rapidly, reversibly and repeatedly be switched on or off by the addition or removal of 4-hydroxytamoxifen (4-HT). 3 Ectopic expression of T-bet-ER in Th2 cells or in T-bet Ϫ/Ϫ Th1 cells in vitro allowed direct examination of the temporal requirements for T-bet activity in regulating three of its target genes, IFN-␥, CD122, and CxCR3.…”

“…1A). Ectopic expression of T-bet is sufficient to induce production of IFN-␥ by otherwise nonpermissive Th2 cells (3,4,23). Therefore, we first examined whether T-bet-ER functions as expected by analyzing transduced Th2 cells.…”