Project description:Lower respiratory viral infections, such as influenza virus and severe acute respiratory syndrome coronavirus 2 infections, often cause severe viral pneumonia in aged individuals. Here, we report that influenza viral pneumonia leads to chronic nonresolving lung pathology and exacerbated accumulation of CD8+ tissue-resident memory T cells (TRM) in the respiratory tract of aged hosts. TRM cell accumulation relies on elevated TGF-β present in aged tissues. Further, we show that TRM cells isolated from aged lungs lack a subpopulation characterized by expression of molecules involved in TCR signaling and effector function. Consequently, TRM cells from aged lungs were insufficient to provide heterologous protective immunity. The depletion of CD8+ TRM cells dampens persistent chronic lung inflammation and ameliorates tissue fibrosis in aged, but not young, animals. Collectively, our data demonstrate that age-associated TRM cell malfunction supports chronic lung inflammatory and fibrotic sequelae after viral pneumonia.
Project description:Cachexia represents a leading cause of morbidity and mortality in various cancers, chronic inflammation and infections. Understanding of the mechanisms that drive cachexia has remained limited, especially for infection-associated cachexia (IAC). In the present paper we describe a model of reversible cachexia in mice with chronic viral infection and identify an essential role for CD8+ T cells in IAC. Cytokines linked to cancer-associated cachexia did not contribute to IAC. Instead, virus-specific CD8+ T cells caused morphologic and molecular changes in the adipose tissue, which led to depletion of lipid stores. These changes occurred at a time point that preceded the peak of the CD8+ T cell response and required T cell-intrinsic type I interferon signaling and antigen-specific priming. Our results link systemic antiviral immune responses to adipose-tissue remodeling and reveal an underappreciated role of CD8+ T cells in IAC.
Project description:IntroductionMucosal immunization eliciting local T-cell memory has been suggested for improved protection against respiratory infections caused by viral variants evading pre-existing antibodies. However, it remains unclear whether T-cell targeted vaccines suffice for prevention of viral transmission and to which extent local immunity is important in this context.MethodsTo study the impact of T-cell vaccination on the course of viral respiratory infection and in particular the capacity to inhibit viral transmission, we used a mouse model involving natural murine parainfluenza infection with a luciferase encoding virus and an adenovirus based nucleoprotein targeting vaccine.Results and discussionPrior intranasal immunization inducing strong mucosal CD8+ T cell immunity provided an almost immediate shut-down of the incipient infection and completely inhibited contact based viral spreading. If this first line of defense did not operate, as in parentally immunized mice, recirculating T cells participated in accelerated viral control that reduced the intensity of inter-individual transmission. These observations underscore the importance of pursuing the development of mucosal T-cell inducing vaccines for optimal protection of the individual and inhibition of inter-individual transmission (herd immunity), while at the same time explain why induction of a strong systemic T-cell response may still impact viral transmission.
Project description:T-cell receptors (TCRs) are formed by stochastic gene rearrangements, theoretically generating >1019 sequences. They are selected during thymopoiesis, which releases a repertoire of about 108 unique TCRs per individual. How evolution shaped a process that produces TCRs that can effectively handle a countless and evolving set of infectious agents is a central question of immunology. The paradigm is that a diverse enough repertoire of TCRs should always provide a proper, though rare, specificity for any given need. Expansion of such rare T cells would provide enough fighters for an effective immune response and enough antigen-experienced cells for memory. We show here that human thymopoiesis releases a large population of clustered CD8+ T cells harboring α/β paired TCRs that (i) have high generation probabilities and (ii) a preferential usage of some V and J genes, (iii) which CDR3 are shared between individuals, and (iv) can each bind and be activated by multiple unrelated viral peptides, notably from EBV, CMV, and influenza. These polyspecific T cells may represent a first line of defense that is mobilized in response to infections before a more specific response subsequently ensures viral elimination. Our results support an evolutionary selection of polyspecific α/β TCRs for broad antiviral responses and heterologous immunity.
Project description:Nucleus accumbens-associated protein 1 (NAC1) is a transcription co-factor that has been shown to possess multiple roles in stem cell and cancer biology. However, little is known about its roles in regulation of the immune system. In the current study, we observed that expression of NAC1 impacted the survival of CD8+ T cells in vitro. NAC1-/- CD8+ T cells displayed lower metabolism, including reduced glycolysis and oxidative phosphorylation. In vivo, compared with wild-type (WT) mice, NAC1-/- mice produced a lower response to vaccinia virus (VACV) infection, and viral antigen (Ag)-specific CD8+ T cells decreased more slowly. Additionally, we observed that the NAC1-/- mice demonstrated a stronger memory formation of viral Ag-specific CD8+ T cells post-viral infection. Mechanically, we identified that compared with WT CD8+ T cells, the Interferon Regulatory Factor 4 (IRF4), a key transcription factor in T cell development, was highly expressed in NAC1-/- CD8+ T cells, insinuating that IRF4 could be a critical regulatory target of NAC1 in the memory formation of CD8+ T cells. Our results indicate that NAC1 restrains the memory formation of CD8+ T cells by modulating IRF4, and targeting NAC1 may be exploited as a new approach to boosting CD8+ T cell memory.
Project description:Chronic infection and cancer are associated with suppressed T cell responses in the presence of cognate antigen. Recent work identified memory-like CXCR5+ TCF1+ CD8+ T cells that sustain T cell responses during persistent infection and proliferate upon anti-PD1 treatment. Approaches to expand these cells are sought. We show that blockade of interferon type 1 (IFN-I) receptor leads to CXCR5+ CD8+ T cell expansion in an IL-27- and STAT1-dependent manner. IFNAR1 blockade promoted accelerated cell division and retention of TCF1 in virus-specific CD8+ T cells. We found that CD8+ T cell-intrinsic IL-27 signaling safeguards the ability of TCF1hi cells to maintain proliferation and avoid terminal differentiation or programmed cell death. Mechanistically, IL-27 endowed rapidly dividing cells with IRF1, a transcription factor that was required for sustained division in a cell-intrinsic manner. These findings reveal that IL-27 opposes IFN-I to uncouple effector differentiation from cell division and suggest that IL-27 signaling could be exploited to augment self-renewing T cells in chronic infections and cancer.
Project description:The cellular origin of CD4- CD8- (double negative, DNT) TCR-α/β+ T cells remains unknown. Available evidence indicates that they may derive from CD8+ T cells, but most published data have been obtained using cells that bear an invariant transgenic T cell receptor that recognizes an Ag that is not present in normal mice. Here, we have used complementary fate mapping and adoptive transfer experiments to identify the cellular lineage of origin of DNT cells in wild-type mice with a polyclonal T cell repertoire. We show that TCR-α/β+ DNT cells can be traced back to CD8+ and CD4+ CD8+ double positive cells in the thymus. We also demonstrate that polyclonal DNT cells generated in secondary lymphoid organs proliferate upon adoptive transfer and can regain CD8 expression in lymphopenic environment. These results demonstrate the cellular origin of DNT cells and provide a conceptual framework to understand their presence in pathological circumstances.
Project description:The role of non-classical T cells during viral infection remains poorly understood. Using the well-established murine model of CMV infection (MCMV) and mice deficient in MHC class Ia molecules, we found that non-classical CD8+ T cells robustly expand after MCMV challenge, become highly activated effectors, and are capable of forming durable memory. Interestingly, although these cells are restricted by MHC class Ib molecules, they respond similarly to conventional T cells. Remarkably, when acting as the sole component of the adaptive immune response, non-classical CD8+ T cells are sufficient to protect against MCMV-induced lethality. We also demonstrate that the MHC class Ib molecule Qa-1 (encoded by H2-T23) restricts a large, and critical, portion of this population. These findings reveal a potential adaptation of the host immune response to compensate for viral evasion of classical T cell immunity.
Project description:Despite recent treatment advances for chronic hepatitis C virus (HCV) infection, a vaccine is urgently needed for global control of this important liver pathogen. The lack of robust immunocompetent HCV infection models makes it challenging to identify correlates of protection and test vaccine efficacy. However, vigorous CD4+ and CD8+ T-cell responses are detected in patients that spontaneously resolve acute infection, whereas dysfunctional T-cell responses are a hallmark of chronic infection. The HCV p7 protein, forming ion-channels essential for viral assembly and release, has not previously been pursued as a vaccine antigen. Herein, we demonstrated that HCV p7 derived from genotype 1a and 1b sequences are highly immunogenic in mice when employed as overlapping peptides formulated as nanoparticles with the cross-priming adjuvant, CAF09. This approach induced multifunctional cytokine producing CD4+ and CD8+ T-cells targeting regions of p7 that are subject to immune pressure during HCV infection in chimpanzees and humans. Employing a surrogate in vivo challenge model of liver cells co-expressing HCV-p7 and GFP, we found that vaccinated mice cleared transgene expressing cells. This study affirms the potential of a T-cell inducing nanoparticle vaccine platform to target the liver and introduces HCV p7 as a potential target for HCV vaccine explorations.
Project description:Crosstalk between T and B cells is crucial for generating high-affinity, class-switched antibody responses. The roles of CD4+ T cells in this process have been well-characterised. In contrast, regulation of antibody responses by CD8+ T cells is significantly less defined. CD8+ T cells are principally recognised for eliciting cytotoxic responses in peripheral tissues and forming protective memory. However, recent findings have identified a novel population of effector CD8+ T cells that co-opt a differentiation program characteristic of CD4+ T follicular helper (Tfh) cells, upregulate the chemokine receptor CXCR5 and localise to B cell follicles. While it has been shown that CXCR5+CD8+ T cells mediate the removal of viral reservoirs in the context of follicular-trophic viral infections and maintain the response to chronic insults by virtue of progenitor/stem-like properties, it is not known if CXCR5+CD8+ T cells arise during acute peripheral challenges in the absence of follicular infection and whether they influence B cell responses in vivo in these settings. Using the ovalbumin-specific T cell receptor transgenic (OT-I) system in an adoptive transfer-immunisation/infection model, this study demonstrates that CXCR5+CD8+ T cells arise in response to protein immunisation and peripheral viral infection, displaying a follicular-homing phenotype, expression of cell surface molecules associated with Tfh cells and limited cytotoxic potential. Furthermore, studies assessing the B cell response in the presence of OT-I or Cxcr5-/- OT-I cells revealed that CXCR5+CD8+ T cells shape the antibody response to protein immunisation and peripheral viral infection, promoting class switching to IgG2c in responding B cells. Overall, the results highlight a novel contribution of CD8+ T cells to antibody responses, expanding the functionality of the adaptive immune system.