Regulating functional cell fates in CD8 T cells

Abstract

The attributes of specificity and memory enable CD8(+) T cells to provide long-lasting protection against a variety of challenges. Although, the importance of CD8(+) T cells for protection against intracellular infections and transformation is well-established, the functional type; effector phenotypes (Tc1, Tc2, Tc17 and/or Tcreg) and/or memory (effector or central), of CD8(+) T cells most desirable for tumor immunity is not established. To determine the tumor efficacy of various effector types and/or memory CD8 T cells, it is imperative to better understand intrinsic and extrinsic factors that regulate CD8(+) T cell differentiation and use this information to generate and test distinct functional cell types in tumor models. The focus of our laboratory investigations is to identify the extrinsic factors such as antigen strength, co-stimulatory molecules, cytokines, and small molecule modifiers that regulate intrinsic programs for various effector and/or memory cell fate in antigen specific CD8 T cells. The use of this information to generate immunity in murine tumor models has facilitated development of new adoptive cell transfer (ACT) as well as immunization strategies for cancer treatment.

Fig. 1

Model for the role of mTOR in sensing extracellular signals and regulating gene programs for effector and memory differentiation of CD8⁺ T cells. Increasing dose of antigen along with inflammatory cytokines promotes heightened mTOR activity leads to sustained T-bet expression. Low dose antigen and/or IL-21, rapamycin induce low levels of mTOR activity leading to decreased mTOR phosphorylation and increased Eomes expression. CD8⁺ T cells expressing high levels of T-bet are dependent on IL-15 for their survival and become effector memory like cells, whereas cells expressing Eomes are intrinsically programmed for central memory-like cells which is IL-7 dependent.