Delineating the role of IL-21 in different phases of CD8+ T cell immune response

Anti-tumour immune responses are largely carried out by cytotoxic immune cells including CD8+ T cells and natural killer (NK) cells. Studies have shown that interleukin-21 (IL-21) can work synergistically with IL-7 or IL-15 to induce proliferation of both memory and naive CD8+ T cells. On its own, IL-21 enhances the production of interferon-gamma (IFNg), perforin and granzyme B (Gzm B), which are the key effector molecules sustaining the cytotoxic activity of CD8+ T cells, via the induction of the transcription factor Tbet. Importantly, IL-21 prevents the exhaustion of CD8+ T cells and is required to control chronic viral infection. In addition, IL-21 was shown to induce the proliferation of NK cells. It also plays a vital role in driving the maturation of NK cells, and thereby enhancing its effector cytotoxic function and IFNg production. Furthermore, IL-21 has been shown to reverse the suppressive effects of regulatory T cells (Treg) on other T cells, ultimately improving the function of effector killer cells. All these pieces of evidence suggest that IL-21 could be a promising target for cancer immunotherapy. Indeed, IL-21 treatment has been tested in various mouse tumour models and several human clinical trials for cancer immunotherapy as single agent or in combination. The results demonstrated that IL-21 treatment boosted the function of CD8+ T cells and NK cells to better control cancers. Though encouraging, further development of IL-21 treatment is limited by our knowledge of how IL-21 treatment exactly regulates anti-tumour immune responses. For example, it remains unclear whether IL-21 treatment primarily enhances the priming of CD8+ T cells or it mostly acts to sustain the function of CD8+ T cells in the post-priming phase. My PhD project focuses on IL-21-mediated regulation on CD8+ T cells and aims to delineate the role of IL-21 in different phases of immune responses. A better understanding of phase-specific function of IL-21 will greatly improve the design and application of IL-21 treatment. By comparing the effect of IL-21 on CD8+ T cell for priming and post-priming function, I found that IL-21 plays a more significant role on post-primed CD8+ T cells by enhancing effector function and also inducing the expression of memory and stem cell-like markers. The phenotypic and metabolic changes induced by IL-21 are distinct from the canonical effector T cell subset induced by IL-2, or memory T cell subset induced by IL-15. I revealed that IL-21-induced CD8+ T cells undergo major metabolic changes towards features reported to be associated with stem cells, which is likely mediated by a signalling pathway via the transcription factor hypoxia-inducible factor 1a (HIF-1a). In summary, IL-21 primarily acts on the post-priming phase of CD8+ T cells and induces a phenotype distinct from canonical effector or memory cells and associated with stem cell-like metabolic change. This discovery opens a new direction for the research of CD8+ T cell differentiation and the application of rationale-based IL-21 therapy