Abstract
CD8+ cytotoxic T lymphocytes are critical components of adaptive immunity against a variety of intracellular pathogens, and can play a key role in the control of tumors. Effective vaccination strategies against viral infections and tumors will likely require the development of potent CD8+ T cell responses, which are constituted by the expansion of robust primary CD8+ T cell populations and the establishment of long-lasting memory. Fully functional CD8+ T cell responses are highly dependent upon CD4+ helper T cells and Signal 3 inflammatory cytokine pathways. CD4+ T cells have been demonstrated to play a critical role in inducing the expression of CD70, the ligand for CD27, on dendritic cells. However, it is not clear to what extent the ‘help’ provided by CD4+ T cells is manifest via CD70, or how CD70-mediated stimulation of CD8+ T cells is integrated with signals that emanate from Signal 3 pathways, such as type-1 interferon (IFN-1) and IL-12. In this work, by enforcing or abrogating CD27 function by genetic or protein intervention in murine models, we sought to identify the function of CD27 costimulation in the activation and fate decisions of CD8+ T cells, to determine the extent it resembles CD4+ T cell help, and how inflammation impacts the relative importance of CD70-CD27 interactions in CD8+ T cell primary responses and CD8+ T cell memory. Both subunit vaccine and replicating/non-replicating viral infection settings have been used to facilitate our comprehensive understanding of the role of CD27 costimulation in CD8+ T cell responses, which has been previously complicated by its variable requirement during different stages of CD8+ T cell responses, depending on the nature of the immunogen. We have demonstrated that in the low inflammatory setting of subunit vaccines, CD27 costimulation synergizes with IFN-1 at the level of CD8+ T cells to achieve robust primary CD8+ T cell responses; while in the high inflammatory setting of replicating viral infection, CD27 costimulation antagonizes with impact of IL-12 to promote CD8+ T cell memory. In addition, we identify CD70-CD27 interactions as one main downstream functional consequence of CD4+ T cell help. Mechanistically, we demonstrate that CD27 costimulation supports CD8+ T cell responses in part by modulating the expression of receptors for ‘fate-decision’ cytokines, including IL-7, IL-12 and likely IL-2. Particularly, IL-7Rα has been identified as a functional marker for memory precursor effector cells, and our data indicate that CD27 signals promote the re-expression of IL-7Rα on effector CD8+ T cells via mRNA regulation. Furthermore, CD27 costimulation strongly induces transcription factor Eomesodermin (Eomes), which is a main contributor of effector function and memory differentiation. Based on this new information, we propose that the interplay between CD27 costimulatory and inflammatory cytokine pathways leads to delicate regulation of transcription factor pair Eomes and T-bet, a critical axis for the activation and fate decisions of CD8+ T cells. In summary, our work has 1) identified complex interactions between Signal 3 and costimulatory pathways, 2) provided insights into the mechanistic basis by which CD27 costimulation influences CD8+ T cell activation and fate decisions, 3) demonstrated a previously unappreciated role of CD27 costimulation as a positive regulator of IL-7Rα during CD8 T cell responses, and 4) highlighted the potential of targeting CD27-CD70 axis for antiviral/antitumor immunotherapy.
