Project Details
Projekt
The role of the transcriptional regulator Lmo4 in CD8+ T cell stemness, memory formation and antitumor immunity
Applicant
Dr. Roland Schelker
Subject Area
Hematology, Oncology
Term
from 2019 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 421981137
Similar to other organ systems, the CD8+ T cell compartment includes cells, which are at different phases of differentiation. In a primary immune response, naive T cells (TN) proceed to T memory stem cells (TSCM), central memory T cells (TCM) and effector memory T cells (TEM), culminating in the genesis of short-lived effector T cells (TEFF). Several pieces of evidence suggest that TSCM have stem cell-like features, more than any other memory T cell population. At the same time, the capability of memory T cells to induce tumor reduction progressively diminishes from TSCM to TCM and TEM. Therefore, discovering strategies that generate and expand TSCM is crucial for the development of the next generation of T cell-based immunotherapies. Various transcriptional networks are used by T cells to facilitate the generation and maintenance of TSCM and to restrict terminal effector differentiation. A potential candidate gene is the transcriptional regulator LIM domain only 4 (Lmo4), which will be the topic of the proposed project. The host laboratory has found that Lmo4 is overexpressed in culture conditions favoring the induction of TSCM. Moreover, they demonstrated that by enforcing the expression of Lmo4 in CD8+ T cells, T cell expansion and memory formation in virus-infected mice was enhanced. Based on the preliminary data, I propose to dissect the role of the transcriptional regulator Lmo4 in CD8+ T cell stemness, memory formation and antitumor immunity. First, the effect of Lmo4 on proliferation and apoptosis of transferred antigen-specific CD8+ T cells will be evaluated following infection of recipient mice with a recombinant strain of vaccinia virus encoding the cognate antigen gp100 (gp100-VV). Furthermore, the frequency of memory precursors and TEFF at peak of the acute immune response and the expression of various cytokines, which are differently expressed in the course of differentiation, will be analyzed. Moreover, the impact of Lmo4 expression on T cell metabolism will be tested and it will be explored if the generation of TSCM could be increased by amplifying Lmo4 expression. Afterwards, the plan is to elucidate downstream effectors of Lmo4 and to evaluate how the genetic manipulation of Lmo4 would affect expression of these genes in the context of CD8+ T cell differentiation. Next, I will evaluate if the enhanced generation of TSCM will promote stronger recall responses after re-challenging mice with an adenovirus encoding gp100 antigen (gp100-Adv) and will determine the efficacy of Lmo4-overexpressing cells adoptively transferred into mice bearing subcutaneous melanomas. To evaluate if the Lmo4-overexpression cohort develop long-lasting antitumor immune responses the animals will be re-challenged with tumors.
DFG Programme
Research Fellowships
International Connection
USA
