The role of the MAZR/Runx3 complex in effector CD8+ T cells

Effector CD8+ T cells play a crucial role in antiviral and antitumor immune responses, and elucidating the molecular mechanisms underlying their differentiation is therefore a fundamental topic in T cell immunology. Transcription factors such as the Runx complex, Eomesodermin, T-bet and others have been shown to regulate effector CD8+ T cell differentiation. We have previously demonstrated that the transcription factor MAZR promotes cell fate choice of double-positive thymocytes into the cytotoxic lineage. Moreover, in ongoing experiments we revealed that MAZR physically interacts with Runx, and that they cooperatively control T cell development. Further, we obtained preliminary evidence that the synergistic activities of MAZR and Runx3 are also required to establish the effector program of CD8+ T cells. In this application, I propose to investigate the role of the MAZR/Runx3 complex during effector CD8+ T cell differentiation. By combining both in vitro and in vivo approaches I will comprehensively analyze the effector function of CD8+ T cells lacking MAZR and/or Runx3. Moreover, I will perform a genome-wide analysis to elucidate the impact of MAZR and Runx3 on global change in gene expression during effector CD8+ T cell differentiation. I believe my study will provide novel insight into the function of MAZR and Runx3 in effector CD8+ T cells, and will significantly advance our understanding of the transcriptional networks governing effector CD8+ T cell differentiation.

CD8+ T cells are an important component of the adaptive immune system. Upon activation they differentiate into "armed" cytotoxic T lymphocytes (CTLs), which play an essential role for anti-viral as well as anti-tumor immunity. Therefore, the elucidation of molecular mechanisms underlying CTL differentiation is a fundamental topic in the field of basic immunology and has a profound impact on clinical research (e.g. therapeutic interventions for viral infection and cancer immunotherapy). With the support of the FWF project P27477, we investigated transcriptional regulation, an important aspect of molecular mechanisms, that controls the generation of CTLs. Based on our previous study, we particularly focused on the two transcription factors, MAZR and Runx3, and investigated their function in CTLs by employing various experimental approaches such as mouse genetic tools, next generation sequencing and an in vivo viral infection model. Our data showed that MAZR plays a compensatory role for Runx3-mediated transcriptional programs in CTLs, and that the combined activity of the two factors are required for appropriate CTL responses. In addition, we expanded our study to investigate their roles in memory T cells (a fraction of CTLs that survives for a longer period and is responsible for recall responses), and found that MAZR restrains the generation of a subset of memory T cells, which is in contrast to the function of Runx3 to promote memory differentiation. Thus, our project revealed a differentiation stage-specific interplay between the two transcription factors and thereby contributed to a better understanding of molecular mechanisms orchestrating the generation of CTLs and memory T cells.