Eomes cannot replace its paralog T-bet during expansion and differentiation of CD8 effector T cells

Abstract

The two T-box transcription factors T-bet and Eomesodermin (Eomes) are important regulators of cytotoxic lymphocytes (CTLs), such as activated CD8 T cells, which are essential in the fight against intracellular pathogens and tumors. Both transcription factors share a great degree of homology based on sequence analysis and as a result exert partial functional redundancy during viral infection. However, the actual degree of redundancy between T-bet and Eomes remains a matter of debate and is further confounded by their distinct spatiotemporal expression pattern in activated CD8 T cells. To directly investigate the functional overlap of these transcription factors, we generated a new mouse model in which Eomes expression is under the transcriptional control of the endogenous Tbx21 (encoding for T-bet) locus. Applying this model, we demonstrate that the induction of Eomes in lieu of T-bet cannot rescue T-bet deficiency in CD8 T cells during acute lymphocytic choriomeningitis virus (LCMV) infection. We found that the expression of Eomes instead of T-bet was not sufficient for early cell expansion or effector cell differentiation. Finally, we show that imposed expression of Eomes after acute viral infection promotes some features of exhaustion but must act in concert with other factors during chronic viral infection to establish all hallmarks of exhaustion. In summary, our results clearly underline the importance of T-bet in guiding canonical CTL development during acute viral infections. According to the World Health Organization infectious diseases kill over 17 million people per year. At the same time highly infectious viral diseases, such as Ebola and COVID-19 that are lacking specific treatments, are emerging to pose additional threats. It is therefore pivotal to precisely understand how our immune system responds towards pathogens to develop new treatment options. Here we have investigated the role of two related molecules, named T-bet and Eomes, that guide the development and function of lymphocytes in their fight against intracellular pathogens. We specifically focused on cytotoxic lymphocytes as these cells dominate the early phase of viral containment. We show that T-bet is essential for the expansion of cytotoxic lymphocytes and equip lymphocytes with the ability to efficiently eliminate virus-infected cells. Hence, our study provides new insights into the importance and specific actions of T-bet during acute viral infections and how this might be harnessed for future therapeutic interventions.