Regulation of T cell exhaustion and PD-1 targeted immunotherapy by mTOR during chronic viral infection
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE215248 | GEO | 2022/12/31
REPOSITORIES: GEO
Similar Datasets
Project description:Chronic viral infections are characterized by a state of CD8 T cell dysfunction termed exhaustion. A better understanding of the mechanisms that regulate CD8 T cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8 T cells. Here we identify a novel population of virus-specific CD8 T cells with a T follicular helper (Tfh)-like signature in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These Tfh-like CD8 T cells expressed the programmed cell death-1 (PD-1) inhibitory receptor but at the same time also expressed co-stimulatory molecules and had a gene signature that was related to CD8 T cell memory precursor cells and hematopoietic stem cells (HSC). These Tfh-like CD8 T cells acted as stem cells during chronic infection undergoing self-renewal and also differentiating into the terminally exhausted CD8 T cells that were present in both lymphoid and non-lymphoid tissues. The Tfh-like CD8 T cells were found only in lymphoid tissues and resided predominantly in the T cell zones along with naïve CD8 T cells. Interestingly, the proliferative burst after PD-1 blockade came almost exclusively from this Tfh-like CD8 T cell subset. Importantly, the transcription factor TCF1 played a cell intrinsic and essential role in the generation of Tfh-like CD8 T cells. Taken together, our study identifies Tfh-like CD8 T cells as the critical subset for maintaining the pool of virus-specific CD8 T cells during chronic infection and as the cells that proliferate after PD-1 blockade. These findings provide a better understanding of T cell exhaustion and have implications towards optimizing PD-1 directed immunotherapy. 8 samples isolated from CD8 T-cells in LCMV clone 13 GK1.5 infected mice (2 naïve, 3 CXCR5+Tim3-, 3 CXCR5-Tim3+) cells were analyzed
2016-08-02 | E-GEOD-84105 | biostudies-arrayexpress
Project description:Inhibitory receptors play a crucial role in regulating CD8 T-cell function during chronic viral infection. T-cell Ig- and mucin-domain-containing molecule-3 (Tim-3) is well known to negatively regulate T-cell responses, but its role in CD8 T-cell exhaustion during chronic infection in vivo remains unclear. In this study, we document coregulation of CD8 T cell exhaustion by Tim-3 and PD-1 during chronic lymphocytic choriomeningitis virus infection. Whereas Tim-3 was only transiently expressed by CD8 T cells after acute infection, virus-specific CD8 T cells retained high Tim-3 expression throughout chronic infection. The majority (approximately 65% to 80%) of lymphocytic choriomeningitis virus-specific CD8 T cells in lymphoid and nonlymphoid organs coexpressed Tim-3 and PD-1. This coexpression of Tim-3 and PD-1 was associated with more severe CD8 T-cell exhaustion in terms of proliferation and secretion of effector cytokines such as IFN-gamma, TNF-alpha, and IL-2. Interestingly, CD8 T cells expressing both inhibitory receptors also produced the suppressive cytokine IL-10. Most importantly, combined blockade of Tim-3 and PD-1 pathways in vivo synergistically improved CD8 T cell responses and viral control in chronically infected mice. Taken together, our study defines a parameter for determining the severity of CD8 T cell dysfunction and for identifying virus-specific CD8 T cells that produce IL-10, and shows that targeting both PD-1 and Tim-3 is an effective immune strategy for treating chronic viral infections.
| S-EPMC2930455 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-06-27 | GSE206739 | GEO
Project description:This work aimed to understand how different IL2 varients
2022-06-27 | GSE206738 | GEO
Project description:In this study we have examined how the cytokine interleukin-2 (IL-2) synergizes with programmed cell death-1 (PD-1) directed immunotherapy during chronic lymphocytic choriomeningitis virus (LCMV) infection. PD-1 blockade in combination with IL-2 is one of the most effective combination therapies in this very stringent LCMV mouse model of life-long chronic infection with irreversible T-cell exhaustion. Our paper makes the following points: First, we show that the more effective viral control seen after PD-1/IL-2 combination therapy compared to PD-1 monotherapy is mediated by the CD8+T-cell response. Then we identify the virus-specific CD8+T cells that proliferate and respond to the combination therapy and show that these are the same lymphoid resident PD-1+TCF-1+stem-like CD8+T cells that act as resource cells to maintain the CD8+T-cell response during chronic infection and also respond to PD-1 blockade. However, the combination therapy dramatically changes the differentiation program of these chronic resource CD8+T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8+T cells that resemble highly functional effector CD8+T cells seen after an acute viral infection. In contrast, PD-1 monotherapy doesnot modify the differentiation program and one gets more virus-specific CD8+T cells but they are transcriptionally and epigenetically similar to what is seen in untreated chronically infected mice. This epigenetic inflexibility of exhausted CD8+T cells is a potential barrier to PD-1 therapy and the ability of this combination therapy to modify the epigenetic signature of virus-specific CD8+T cells during chronic infection could be an important determinant of the striking synergy seen between IL-2 therapy and PD-1 blockade. We also highlight the importance of blocking the PD-1/PD-L1 inhibitory pathway at the target site for effective viral control. Expanding the CD8+ Tcell population and generating better effector cells is important but it is also critical to block PD-1 inhibitory signals at the target site for optimal immunotherapy. Finally, we show that CD25 engagement with IL-2 plays an important and essential role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind CD25 but still binds CD122/132 almost completely abrogated the synergistic effects seen after PD-1/IL-2 combination therapy. There is currently considerable interest in PD-1/IL-2 combination therapy for cancer patients and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.
2022-06-27 | GSE206732 | GEO
Project description:This work aimed to understand how different IL2 varients
2022-06-27 | GSE206821 | GEO
Project description:Patients who survive sepsis display suppressed immune functions, often manifested as an increased susceptibility to secondary infections. Recently, using a cecal-ligation and puncture (CLP) model of sepsis, we showed that sepsis induces substantial and long-lasting changes in the available naive CD8(+) T cell repertoire affecting the capacity of the host to respond to newly encountered acute infections. However, the extent to which sepsis changes the host susceptibility to chronic infection and affects CD8(+) T cell responses is currently unknown. In this study, we demonstrate that inbred and outbred mice recovering from a septic event are more susceptible to lymphocytic choriomeningitis virus (LCMV) clone-13 infection exhibited by mortality and viral burden. Primary virus-specific CD8(+) T cells in LCMV clone-13-infected septic mice displayed exacerbated CD8(+) T cell exhaustion illustrated by increased inhibitory molecule expression (e.g., programmed cell death 1, lymphocyte-activation gene 3, and 2B4) and diminished Ag-driven cytokine production (e.g., IFN-?, TNF-?) compared with similarly infected sham-treated mice. Importantly, therapeutic inhibitory molecule dual blockade (anti-PD-L1 and anti-lymphocyte-activation gene 3) increased the number of circulating LCMV-specific CD8(+) T cells, and improved CD8(+) T cell function and pathogen control in chronically infected septic mice. Together, these results illustrate that polymicrobial sepsis compromises the overall health of the host leading to increased vulnerability to chronic infection and exacerbated CD8(+) T cell exhaustion. Collectively, our findings suggest that septic survivors may be more susceptible and at greater risk for developing exhaustible CD8(+) T cells upon encountering a subsequent chronic infection.
| S-EPMC4475506 | biostudies-literature
Project description:T cell exhaustion often occurs during chronic infection and prevents optimal viral control. The molecular pathways involved in T cell exhaustion remain poorly understood. Here we show that exhausted CD8+ T cells are subject to complex layers of negative regulation resulting from the coexpression of multiple inhibitory receptors. Exhausted CD8+ T cells expressed up to seven inhibitory receptors. Coexpression of multiple distinct inhibitory receptors was associated with greater T cell exhaustion and more severe infection. Regulation of T cell exhaustion by various inhibitory pathways was nonredundant, as blockade of the T cell inhibitory receptors PD-1 and LAG-3 simultaneously and synergistically improved T cell responses and diminished viral load in vivo. Thus, CD8+ T cell responses during chronic viral infections are regulated by complex patterns of coexpressed inhibitory receptors.
| S-EPMC2605166 | biostudies-literature
Project description:Many persistent viral infections induce dysfunctional T cell responses. Although a negative correlation exists between viral load and T cell responses during chronic infection, it is not known whether high antigen levels are the cause or just the consequence of T cell exhaustion. Furthermore, it is unclear what role antigen presentation by bone-marrow (BM) derived versus infected parenchymal cells has on T cell exhaustion. To address these issues, we examined the influence of antigen presentation by different cell types on CD8(+) T cell responses during persistent infection of mice with lymphocytic choriomeningitis virus (LCMV) clone 13. We generated BM chimeric mice, in which non-BM derived cells were MHC class I deficient. Virus-specific CD8(+) T cells in lymphoid and nonlymphoid tissues were increased in both number and ability to produce cytokines in these mice soon after infection. However, viral clearance from infected MHC I(-/-) parenchyma was significantly impaired, despite increased populations of cytokine producing CTL. The CD8(+) T cell response was overwhelmed by sustained antigen persistence, becoming increasingly exhausted within 4-6 weeks. Thus, we find that (i) sustained antigen presentation directly drives T cell exhaustion during a chronic viral infection, (ii) CTL require direct antigen-MHC interactions to clear virus-infected cells, and (iii) persistent interactions with antigen presented on both hematopoietic and nonhematopoietic cells negatively impacts virus-specific T cell responses during chronic infection.
| S-EPMC2688997 | biostudies-literature
Project description:This work aimed to understand how different IL2 varients
2022-06-27 | GSE206722 | GEO