Abstract
Tumor antigen–primed CD8 T cells differentiate into effector T cells that kill tumor cells rapidly, whereas durable responses of CD8 T cells are required to cope with long-lasting tumor growth. However, it is not well known how persisting CD8 T cells are generated. In this study, we analyzed CD8 T cells primed by antigens in tumor-draining lymph nodes and found that CD8 T cells first differentiated into a CD62L-intermediate (CD62Lint) stage upon antigen stimulation. These cells gave rise to tumor-infiltrating CD62L-CD44high Bcl6- effector T cells and CD62L+CD44highBcl6+ memory-like T cells. Memory-like T cells within the tumor expressed CD127, CXCR3 and had the potential to proliferate significantly when they were transferred into tumor-bearing mice. Bcl6 expression in these T cells was critical because Bcl6-/-CD62L+CD44highCD8T cells within the tumor were defective in expansion after secondary transfer. Taken together, our findings show that CD62L+CD44highBcl6+ cells are generated from highly proliferating CD62Lint T cells and retain high proliferative potential, which contributes to replenishment of effector T cells within the tumor.
Highlights
Antigen priming of CD8 T cells is crucial to induce effector T cells that eliminate viral infections and tumor cells
Transferring CD62L+ tumor-infiltrating cells with B cell lymphoma 6 protein (Bcl6) deficiency resulted in a significant reduction in both frequencies and cell numbers in the recipient mice (Fig 4D and 4E). These results demonstrated that Bcl6 expression in CD62L+ tumor-infiltrating cells is relevant to their ability to expand
These results suggested that CD62L+Bcl6+ tumor-infiltrating CD8 T cells had more potential to kill tumor cells than CD62L-Bcl6- cells when they were transferred
Summary
Antigen priming of CD8 T cells is crucial to induce effector T cells that eliminate viral infections and tumor cells. Following contraction of the effector T cell population, a limited number of T cells are maintained as memory T cells. Antigen-primed CD8 T cells exhibit transcriptional divergence in the progeny of their first division [2]. Factors that drive the effector versus memory CD8 T cells could be signal strength through TCR stimulation [3] and cytokines such as IL-2 [4] and IL-15 [5]. In anti-tumor CD8 T cell responses, as well as in chronic viral infection, persistent antigens promote altered T cell differentiation, resulting in generation of effector T cells with memory
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