T-Bet and Eomes Regulate the Balance between the Effector/Central Memory T Cells versus Memory Stem Like T Cells

PLOS ONE, Dec 2019

Memory T cells are composed of effector, central, and memory stem cells. Previous studies have implicated that both T-bet and Eomes are involved in the generation of effector and central memory CD8 T cells. The exact role of these transcription factors in shaping the memory T cell pool is not well understood, particularly with memory stem T cells. Here, we demonstrate that both T-bet or Eomes are required for elimination of established tumors by adoptively transferred CD8 T cells. We also examined the role of T-bet and Eomes in the generation of tumor-specific memory T cell subsets upon adoptive transfer. We showed that combined T-bet and Eomes deficiency resulted in a severe reduction in the number of effector/central memory T cells but an increase in the percentage of CD62LhighCD44low Sca-1+ T cells which were similar to the phenotype of memory stem T cells. Despite preserving large numbers of phenotypic memory stem T cells, the lack of both of T-bet and Eomes resulted in a profound defect in antitumor memory responses, suggesting T-bet and Eomes are crucial for the antitumor function of these memory T cells. Our study establishes that T-bet and Eomes cooperate to promote the phenotype of effector/central memory CD8 T cell versus that of memory stem like T cells.

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T-Bet and Eomes Regulate the Balance between the Effector/Central Memory T Cells versus Memory Stem Like T Cells

et al. (2013) T-Bet and Eomes Regulate the Balance between the Effector/Central Memory T Cells versus Memory Stem Like T Cells. PLoS ONE 8(6): e67401. doi:10.1371/journal.pone.0067401 T-Bet and Eomes Regulate the Balance between the Effector/Central Memory T Cells versus Memory Stem Like T Cells Gang Li 0 Qianting Yang 0 Yibei Zhu 0 Hong-Rui Wang 0 Xinchun Chen 0 Xueguang Zhang 0 Binfeng Lu 0 Mehrdad Matloubian, University of California, San Francisco, United States of America 0 1 Stem Cell Research Laboratory of Jiangsu Province, Jiangsu Institute of Clinical Immunology, Institute of Medical Biotechnology, Soochow University , Suzhou, Jiangsu , China , 2 Department of Immunology, University of Pittsburgh School of Medicine , Pittsburgh , Pennsylvania, United States of America, 3 Guangdong Key Lab for Emerging Infectious Disease, Shenzhen Key Lab of Infection and Immunity, Third People's Hospital, Guangdong Medical College , Shenzhen, Guangdong , China , 4 Department of Immunology, Medical College of Soochow University , Suzhou, Jiangsu , China , 5 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University , Xiamen, Fujian , China Memory T cells are composed of effector, central, and memory stem cells. Previous studies have implicated that both T-bet and Eomes are involved in the generation of effector and central memory CD8 T cells. The exact role of these transcription factors in shaping the memory T cell pool is not well understood, particularly with memory stem T cells. Here, we demonstrate that both T-bet or Eomes are required for elimination of established tumors by adoptively transferred CD8 T cells. We also examined the role of T-bet and Eomes in the generation of tumor-specific memory T cell subsets upon adoptive transfer. We showed that combined T-bet and Eomes deficiency resulted in a severe reduction in the number of effector/central memory T cells but an increase in the percentage of CD62LhighCD44low Sca-1+ T cells which were similar to the phenotype of memory stem T cells. Despite preserving large numbers of phenotypic memory stem T cells, the lack of both of T-bet and Eomes resulted in a profound defect in antitumor memory responses, suggesting T-bet and Eomes are crucial for the antitumor function of these memory T cells. Our study establishes that T-bet and Eomes cooperate to promote the phenotype of effector/central memory CD8 T cell versus that of memory stem like T cells. - Funding: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work is supported by 1R21CA167229-01A1 to BL. GL is partly supported by a scholarship from NSFC (#2010692006). This work is partly supported by NSFC key grant 30930085, the 973 project (No. 2013CB530501) and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institution (PAPD) (to XG. Zhang). Y Zhu is supported by NSFC grant 31170866, 81273208 and Jiangsu natural science fund BK2011289. QY and XC are supported by National Nature Science Foundation of China Grant No.81171535. Competing Interests: The authors have declared that no competing interests exist . These authors contributed equally to this work. Tumor growth can elicit type 1 cellular immune responses that limit cancer progression. Ample clinical evidence shows that longer survival of cancer patients is associated with increased expression of genes characteristic of type 1 effector T cells, in particular master transcription regulators T-bet and Eomes. [15] In T cells, T-bet and Eomes are regulated by cytokines with divergent functions and therefore have overlapping as well as distinct functions [611]. IL-12 and IFN-c drive T-bet expression, [12,13] and IL-2 promotes Eomes expression. [7,14,15] T-bet and Eomes play an additive role in driving IFN-c production and cytotoxic activities of effector CD8 T cells in vitro. [8,16] T-bet and Eomes also coordinately promote T cell migration to inflamed tissues by inducing chemokine receptors. [16,17] In addition, Tbet and Eomes control the expression of CD122 and are required for maintenance of IL-15-dependent memory CD8 T cells. [10,11] High T-bet expression promotes short-lived effector CD8 T cells, whereas low T-bet expression promotes long-lived memory cells. [18], [6,11,19] Thus, T-bet and Eomes are important for both function and homeostasis of effector and memory T cells. However, the role of T-bet and Eomes in the setting of memory T cell responses to tumor antigens is unknown. The memory T cells have been typically divided into two main subsets based on the expression of the lymph node homing molecules CD62L and CCR7. [20] Central memory T cells (TCM) express high levels of CD62L and CCR7, whereas effector memory T cells (TEM) express low levels of CD62L and CCR7. Recent studies demonstrated the existence of a new population of memory T cells designated T memory stem cells (TSCM) [21] [22]. (...truncated)


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Gang Li, Qianting Yang, Yibei Zhu, Hong-Rui Wang, Xinchun Chen, Xueguang Zhang, Binfeng Lu. T-Bet and Eomes Regulate the Balance between the Effector/Central Memory T Cells versus Memory Stem Like T Cells, PLOS ONE, 2013, Volume 8, Issue 6, DOI: 10.1371/journal.pone.0067401