Cyclophilin D Regulates Antiviral CD8+ T Cell Survival in a Cell-Extrinsic Manner

CD8+ T cell–mediated immunity is critical for host defense against viruses and requires mitochondria-mediated type I IFN (IFN-I) signaling for optimal protection. Cyclophilin D (CypD) is a mitochondrial matrix protein that modulates the mitochondrial permeability transition pore, but its role in IFN-I signaling and CD8+ T cell responses to viral infection has not been previously explored. In this study, we demonstrate that CypD plays a critical extrinsic role in the survival of Ag-specific CD8+ T cell following acute viral infection with lymphocytic choriomeningitis virus in mice. CypD deficiency resulted in reduced IFN-I and increased CD8+ T cell death, resulting in a reduced antiviral CD8+ T cell response. In addition, CypD deficiency was associated with an increase in pathogen burden at an early time-point following infection. Furthermore, our data demonstrate that transfer of wild-type macrophages (expressing CypD) to CypD-deficient mice can partially restore CD8+ T cell responses. These results establish that CypD plays an extrinsic role in regulating optimal effector CD8+ T cell responses to viral infection. Furthermore, this suggests that, under certain circumstances, inhibition of CypD function may have a detrimental impact on the host’s ability to respond to viral infection

Pre-existing chromatin accessibility and gene expression differences among naive CD4+ T cells influence effector potential

CD4+ T cells have a remarkable potential to differentiate into diverse effector lineages following activation. Here, we probe the heterogeneity present among naive CD4+ T cells before encountering their cognate antigen to ask whether their effector potential is modulated by pre-existing transcriptional and chromatin landscape differences. Single-cell RNA sequencing shows that key drivers of variability are genes involved in T cell receptor (TCR) signaling. Using CD5 expression as a readout of the strength of tonic TCR interactions with self-peptide MHC, and sorting on the ends of this self-reactivity spectrum, we find that pre-existing transcriptional differences among naive CD4+ T cells impact follicular helper T (TFH) cell versus non-TFH effector lineage choice. Moreover, our data implicate TCR signal strength during thymic development in establishing differences in naive CD4+ T cell chromatin landscapes that ultimately shape their effector potential

The immune battlefield: The impact of inflammatory cytokines on CD8⁺ T-cell immunity - Fig 1

<p><b>A.</b> CD8⁺ T-cell basics: upon integrating the 3 signals needed for activation (1, TCR; 2, costimulation; 3, cytokines), a naïve antigen-specific CD8⁺ T cell clonally expands, acquires effector functions to kill invading pathogen, and then undergoes numerical contraction, developing into long-lived protective memory antigen-specific CD8⁺ T cells. <b>B</b>. Memory CD8⁺ T-cell exposure to proinflammatory cytokines (i.e., IL-12, IL-15, IFN-I) enhances their function, allowing them to counteract and neutralize pathogen risk. <b>C.</b> Virus-mediated inhibition of IFN-I production leads to dysfunctional CD8⁺ T-cell responses and pathogen persistence. <b>D</b>. Transient IL-10 does not impair functional CD8⁺ T-cell responses, allowing pathogen control and clearance. Sustained IL-10 production leads to CD8⁺ T-cell dysfunction and pathogen persistence. <b>E</b>. Inflammation influences memory CD8⁺ T-cell generation, impacting vaccine development and protective immunity. IFN, interferon; IL, interleukin; MPEC, memory precursor effector cell; SLEC, short-lived effector cell; TCR, T-cell receptor.</p

Coxsackievirus B3 elicits a sex-specific CD8+ T cell response which protects female mice.

Sex is a significant contributor to the outcome of human infections. Males are frequently more susceptible to viral, bacterial, and fungal infections, often attributed to weaker immune responses. In contrast, a heightened immune response in females enables better pathogen elimination but leaves females more predisposed to autoimmune diseases. Unfortunately, the underlying basis for sex-specific immune responses remains poorly understood. Here, we show a sex difference in the CD8+ T cell response to an enteric virus, Coxsackievirus B3 (CVB3). We found that CVB3 induced expansion of CD8+ T cells in female mice but not in male mice. CVB3 also increased the proportion and number of CD11ahiCD62Llo CD8+ T cells in female mice, indicative of activation. This response was independent of the inoculation route and type I interferon. Using a recombinant CVB3 virus expressing a model CD8+ T cell epitope, we found that the expansion of CD8+ T cells in females is viral-specific and not due to bystander activation. Finally, the depletion of CD8+ T cells, prior to infection, led to enhanced mortality, indicating that CD8+ T cells are protective against CVB3 in female mice. These data demonstrate that CVB3 induces a CD8+ T cell response in female mice and highlight the importance of sex-specific immune responses to viral pathogens

Analysis of the T Cell Response to Zika Virus and Identification of a Novel CD8⁺ T Cell Epitope in Immunocompetent Mice

<div><p>Zika virus (ZIKV) is an emerging arbovirus of the <i>Flaviviridae</i> family. Although ZIKV infection is typically mild and self-limiting in healthy adults, infection has been associated with neurological symptoms such as Guillain-Barré syndrome, and a causal link has been established between fetal microcephaly and ZIKV infection during pregnancy. These risks, and the magnitude of the ongoing ZIKV pandemic, have created an urgent need for the development of animal models to study the immune response to ZIKV infection. Previous animal models have primarily focused on pathogenesis in immunocompromised mice. In this study, we provide a model of ZIKV infection in wild-type immunocompetent C57BL/6 mice, and have provided an analysis of the immune response to infection. We evaluated the activation of several innate immune cell types, and studied the kinetics, phenotype, and functionality of T cell responses to ZIKV infection. Our results demonstrate that ZIKV infection is mild in wild-type immunocompetent C57BL/6 mice, resulting in minimal morbidity. Our data establish that at the peak of the adaptive response, antigen-experienced CD4⁺ T cells polarize to a Th1 phenotype, and antigen-experienced CD8⁺ T cells exhibit an activated effector phenotype, producing both effector cytokines and cytolytic molecules. Furthermore, we have identified a novel ZIKV CD8⁺ T cell epitope in the envelope protein that is recognized by the majority of responding cells. Our model provides an important reference point that will help dissect the impact of polymorphisms in the circulating ZIKV strains on the immune response and ZIKV pathogenesis. In addition, the identification of a ZIKV epitope will allow for the design of tetramers to study epitope-specific T cell responses, and will have important implications for the design and development of ZIKV vaccine strategies.</p></div