Search

CD8+ T cells are key in mediating immune responses to viral infections. Viral infections can be acute, in which the infection is resolved, or chronic, when antigen persists. Several studies have illustrated that CD8+ T cells adopt distinct functional states in each infection type. In acute infections, naïve CD8+T cells differentiate into cytotoxic CD8+ T cells and memory CD8+ T cells. In chronic infections, activated CD8+ T cells adopt an altered state known as exhaustion. Exhausted CD8+ T cells lose effector functions and show high expression of inhibitory receptors such as PD-1. Several studies have characterized CD8+ T cell exhaustion at late time-points after a persistent infection has already been established. Recent studies demonstrate that CD8+ T cell exhaustion may be specified during earlier phases of a developing chronic infection. However, these studies do not address the effect of biological sex on early CD8+ T cell responses to chronic infection. Sex differences in susceptibility and outcomes of viral infectious diseases are well-appreciated. Still, the role of sex in the development of CD8+ T cell exhaustion and in the molecular programs underlying CD8+ T cell responses to acute and chronic viral infections remains undefined. This study, therefore, set out to investigate early and sex-based differences in the transcriptional profiles of CD8+ T cells that underlie their responses to acute versus chronic viral infection. The mouse model of acute and chronic lymphocytic choriomeningitis virus infection was used to comparatively analyze transcriptional signatures of single antigen-specific CD8+ T cells during acute versus chronic infection at multiple time-points post-infection. Next sequencing coupled with bioinformatics-based approaches were used to analyze our single-cell RNA sequencing data. Our results reveal an early transcriptional divergence of CD8+ T cells responding to acute versus chronic viral infection. We show that there are sex-specific diff

CD8+ T cells are key in mediating immune responses to viral infections. Viral infections can be acute, in which the infection is resolved, or chronic, when antigen persists. Several studies have illustrated that CD8+ T cells adopt distinct functional states in each infection type. In acute infections, naïve CD8+T cells differentiate into cytotoxic CD8+ T cells and memory CD8+ T cells. In chronic infections, activated CD8+ T cells adopt an altered state known as exhaustion. Exhausted CD8+ T cells lose effector functions and show high expression of inhibitory receptors such as PD-1. Several studies have characterized CD8+ T cell exhaustion at late time-points after a persistent infection has already been established. Recent studies demonstrate that CD8+ T cell exhaustion may be specified during earlier phases of a developing chronic infection. However, these studies do not address the effect of biological sex on early CD8+ T cell responses to chronic infection. Sex differences in susceptibility and outcomes of viral infectious diseases are well-appreciated. Still, the role of sex in the development of CD8+ T cell exhaustion and in the molecular programs underlying CD8+ T cell responses to acute and chronic viral infections remains undefined. This study, therefore, set out to investigate early and sex-based differences in the transcriptional profiles of CD8+ T cells that underlie their responses to acute versus chronic viral infection. The mouse model of acute and chronic lymphocytic choriomeningitis virus infection was used to comparatively analyze transcriptional signatures of single antigen-specific CD8+ T cells during acute versus chronic infection at multiple time-points post-infection. Next sequencing coupled with bioinformatics-based approaches were used to analyze our single-cell RNA sequencing data. Our results reveal an early transcriptional divergence of CD8+ T cells responding to acute versus chronic viral infection. We show that there are sex-specific diff

T lymphocytes are critical components of the adaptive immune system that protects us against a variety of infections. However, during chronic infections such as with HIV, HCV and HBV as well as cancers, T cells become functionally impaired in order to limit immunopathology. This in turn allows these infections to persist or tumours to grow and spread. Scientific research over the last decades lead to the development of checkpoint inhibitors which can reinvigorate exhausted CD8+ T cells. This enables them to fight persisting infections and to eliminate even advanced tumours. Based on this success, checkpoint immunotherapy has revolutionized cancer treatment. With the identification of the memory-like TCF-1+ subset of exhausted CD8+ T cells that responds to checkpoint immunotherapy, predictions for clinical responses can be further improved. Yet, despite the enormous success and routine application, a deeper mechanistic understanding of checkpoint immunotherapy is required in order to help patients in whom this therapy failed. In this study, we elucidate critical cellular interaction partners of exhausted CD8+ T cells during anti-PD-L1 treatment. Using the murine chronic LCMV model, we found that DC with their key function in T cell activation are pivotal for a successful therapy demonstrated by the expansion of virus-specific CD8+ T cells and control of viral load. Notably, different DC subsets represent complementary roles in this context. The cross-presenting subset of XCR1+ DC are critical to maintain the population of memory-like TCF-1+ exhausted CD8+ T cells while the remaining DC promote proliferation of such. Data presented in this study indicate that a complex network of signalling molecules delivered by DC subsets is involved in this process. Performing detailed transcriptional analysis of memory-like TCF-1+ cells, we deciphered that this cell pool represents a heterogenous population and our results imply that the different subsets reside in different areas