CD8 T cells mediate protection against intracellular pathogens and tumors. However, persistent antigen during chronic infections or cancer leads to T cell exhaustion, suboptimal functionality, and ...reduced protective capacity. Despite considerable work interrogating the transcriptional regulation of exhausted CD8 T cells (TEX), the posttranscriptional control of TEX remains poorly understood. Here, we interrogated the role of microRNAs (miRs) in CD8 T cells responding to acutely resolved or chronic viral infection and identified miR-29a as a key regulator of TEX. Enforced expression of miR-29a improved CD8 T cell responses during chronic viral infection and antagonized exhaustion. miR-29a inhibited exhaustion-driving transcriptional pathways, including inflammatory and T cell receptor signaling, and regulated ribosomal biogenesis. As a result, miR-29a fostered a memory-like CD8 T cell differentiation state during chronic infection. Thus, we identify miR-29a as a key regulator of TEX and define mechanisms by which miR-29a can divert exhaustion toward a more beneficial memory-like CD8 T cell differentiation state.
The innate and adaptive immune systems fail to control HCV infection in the majority of infected individuals. HCV is an ssRNA virus, which suggests a role for Toll-like receptors (TLRs) 7 and 8 in ...initiating the anti-viral response. Here we demonstrate that HCV genomic RNA harbours specific sequences that initiate an anti-HCV immune response through TLR7 and TLR8 in various antigen presenting cells. Conversely, HCV particles are detected by macrophages, but not by monocytes and DCs, through a TLR7/8 dependent mechanism; this leads to chloroquine sensitive production of pro-inflammatory cytokines including IL-1β, while the antiviral type I Interferon response is not triggered in these cells. Antibodies to DC-SIGN, a c-type lectin selectively expressed by macrophages but not pDCs or mDCs, block the production of cytokines. Novel anti-HCV vaccination strategies should target the induction of TLR7/8 stimulation in APCs in order to establish potent immune responses against HCV.
Hepatitis C virus (HCV) affects more than 268,000 people in Canada. Both the Canadian Institutes of Health Research and the Public Health Agency of Canada recognize the significant impact of ...HCV-related liver diseases and supported the establishment of a national hepatitis C research network, the Canadian Network on Hepatitis C (CanHepC). Interferon-free direct-acting antiviral regimens lead to more than 95% cure rates in almost all patients with well-tolerated short-course therapy. However, the goal of eliminating HCV in Canada cannot be fully realized until we overcome the financial, geographical, cultural, and social barriers that affect the entire continuum of care from diagnosis and linkage to care through treatment and prevention of new and reinfections. Current practices face difficulties in reversing HCV-induced immunological defects, expanding treatment to neglected communities, combating reinfections and co-infections, and expediting and simplifying the processes of diagnosis and treatment. As part of its knowledge translation mandate, CanHepC has organized the annual Canadian symposium on hepatitis C since 2012. The theme of this year’s symposium, “Toward Elimination of HCV: How to Get There?” focused on identifying the requirements of our therapeutic strategies and health policies for the elimination of HCV in Canada.
Abstract
Exhaustion gradually establishes in chronically stimulated CD8s and this process is not reverted by current therapeutic approaches due to establishment of a stable epigenetic program. Recent ...advances have informed on the developmental process of exhaustion and highlighted TOX as a key lineage-defining TF in the process. Yet, little remains known on molecular pathways capable of antagonizing the TOX-dependent exhaustion program. By depicting transcriptional changes at key developmental steps of exhaustion, we demonstrate an antagonistic role for the TF STAT5 in the development of CD8 T cell exhaustion. STAT5 transcriptional network is heavily silenced upon chronic antigenic stimulation in a TOX-dependent manner which allows initiation of the exhaustion lineage. Increasing STAT5 activity abrogates establishment of the exhaustion lineage leading to the development of effector-like CD8s that acquire a unique transcriptional identity, distinct from exhausted cells, persist throughout chronicity and demonstrate higher protective capacity. Using temporal loss and gain of function approaches, we show that STAT5 triggers loss of progenitor identity by exhausted CD8s (Tex) and subsequent differentiation into the recently identified effector-like intermediate Tex subset. Temporal increase in STAT5 activity also robustly synergizes with PD-L1 blockade by further fostering intermediate Tex cells accumulation. Together, we show that modulating STAT5 activity may counteract the exhaustion process and favor instigation of effector-like characteristic in Tex cells suitable for optimal therapeutic efficacy.
This work is supported by the Parker Institute for Cancer Immunotherapy (PICI). JC-Beltra is a PICI scholar awardee.
Abstract
Exhausted CD8 T cells (TEX) are essential during chronic viral infections and cancer. Two TEX subpopulations including a progenitor and a more terminally exhausted subset cooperate to ...maintain an active immune response during antigen persistence. However, non-overlapping delineations of these populations have suggested a more complex developmental biology. Here, using the LCMV mouse model of chronic viral infection, we identify four distinct TEX subsets based on Ly108 (Slamf6) and CD69 expression revealing a novel stepwise developmental framework. We reveal the transcriptional and epigenetic control mechanisms and associated biological changes underlying each TEX subset transition. Two TCF1+ progenitors were identified along with a novel TCF1-intermediate subset that re-engaged some aspects of effector biology. This subset depended on T-bet and was re-invigorated upon PD-L1 blockade. Ultimately, Tox coordinated loss of T-bet and differentiation into a fourth, terminally exhausted subset. These data define a new developmental hierarchy of TEX and reveal distinct biological properties with direct relevance to immunotherapy. Defining the control mechanisms of this TEX subset hierarchy provides novel opportunities to manipulate TEX biology for clinical goals.
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