scholarly journals Differential Tissue-Specific Regulation of Antiviral CD8+ T-Cell Immune Responses during Chronic Viral Infection

2004 ◽  
Vol 78 (7) ◽  
pp. 3578-3600 ◽  
Author(s):  
Shenghua Zhou ◽  
Rong Ou ◽  
Lei Huang ◽  
Graeme E. Price ◽  
Demetrius Moskophidis
Keyword(s):  
T Cell ◽  
Viral Infection ◽  
Viral Infections ◽  
Lymphoid Tissues ◽  
Control Mechanisms ◽  
Chronic Infections ◽  
Tissue Specific ◽  
Specific Ctls ◽  
Specific Regulation ◽  
Differential Tissue

ABSTRACT The hallmarks of the immune response to viral infections are the expansion of antigen-specific CD8+ cytotoxic T lymphocytes (CTLs) after they encounter antigen-presenting cells in the lymphoid tissues and their subsequent redistribution to nonlymphoid tissues to deal with the pathogen. Control mechanisms exist within CTL activation pathways to prevent inappropriate CTL responses against disseminating infections with a broad distribution of pathogen in host tissues. This is demonstrated during overwhelming infection with the noncytolytic murine lymphocytic choriomeningitis virus, in which clonal exhaustion (anergy and/or deletion) of CTLs prevents immune-mediated pathology but allows persistence of the virus. The mechanism by which the immune system determines whether or not to mount a full response to such infections is unknown. Here we present data showing that the initial encounter of specific CTLs with infected cells in lymphoid tissues is critical for this decision. Whether the course of the viral infection is acute or persistent for life primarily depends on the degree and kinetics of CTL exhaustion in infected lymphoid tissues. Virus-driven CTL expansion in lymphoid tissues resulted in the migration of large quantities of CTLs to nonlymphoid tissues, where they persisted at stable levels. Surprisingly, although virus-specific CTLs were rapidly clonally exhausted in lymphoid tissues under conditions of chronic infection, a substantial number of them migrated to nonlymphoid tissues, where they retained an effector phenotype for a long time. However, these cells were unable to control the infection and progressively lost their antiviral capacities (cytotoxicity and cytokine secretion) in a hierarchical manner before their eventual physical elimination. These results illustrate the differential tissue-specific regulation of antiviral T-cell responses during chronic infections and may help us to understand the dynamic relationship between antigen and T-cell populations in many persistent infections in humans.

scholarly journals Endogenous glucocorticoids control host resistance to viral infection through the tissue-specific regulation of PD-1 expression on NK cells

2018 ◽  
Vol 19 (9) ◽  
pp. 954-962 ◽  
Author(s):  
Linda Quatrini ◽  
Elisabeth Wieduwild ◽  
Bertrand Escaliere ◽  
Jessica Filtjens ◽  
Lionel Chasson ◽  
...  
Keyword(s):  
Viral Infection ◽  
Nk Cells ◽  
Host Resistance ◽  
Tissue Specific ◽  
Specific Regulation ◽  
Resistance To Viral Infection

scholarly journals Viral infection prevents diabetes by inducing regulatory T cells through NKT cell–plasmacytoid dendritic cell interplay

2011 ◽  
Vol 208 (4) ◽  
pp. 729-745 ◽  
Author(s):  
Julien Diana ◽  
Vedran Brezar ◽  
Lucie Beaudoin ◽  
Marc Dalod ◽  
Andrew Mellor ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Regulatory T Cells ◽  
Viral Infection ◽  
Pancreatic Islets ◽  
Viral Infections ◽  
Plasmacytoid Dendritic Cell ◽  
Inkt Cells ◽  
Pancreatic Lymph Nodes

Type 1 diabetes (T1D) is an autoimmune disease resulting from T cell–mediated destruction of insulin-producing β cells, and viral infections can prevent the onset of disease. Invariant natural killer T cells (iNKT cells) exert a regulatory role in T1D by inhibiting autoimmune T cell responses. As iNKT cell–plasmacytoid dendritic cell (pDC) cooperation controls viral replication in the pancreatic islets, we investigated whether this cellular cross talk could interfere with T1D development during viral infection. Using both virus-induced and spontaneous mouse models of T1D, we show that upon viral infection, iNKT cells induce TGF-β–producing pDCs in the pancreatic lymph nodes (LNs). These tolerogenic pDCs convert naive anti-islet T cells into Foxp3+ CD4+ regulatory T cells (T reg cells) in pancreatic LNs. T reg cells are then recruited into the pancreatic islets where they produce TGF-β, which dampens the activity of viral- and islet-specific CD8+ T cells, thereby preventing T1D development in both T1D models. These findings reveal a crucial cooperation between iNKT cells, pDCs, and T reg cells for prevention of T1D by viral infection.

scholarly journals Tissue-Specific Differences in PD-1 and PD-L1 Expression during Chronic Viral Infection: Implications for CD8 T-Cell Exhaustion

2009 ◽  
Vol 84 (4) ◽  
pp. 2078-2089 ◽  
Author(s):  
Shawn D. Blackburn ◽  
Alison Crawford ◽  
Haina Shin ◽  
Antonio Polley ◽  
Gordon J. Freeman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Therapeutic Interventions ◽  
Chronic Viral Infection ◽  
Anatomical Location ◽  
T Cell Exhaustion ◽  
Tissue Specific ◽  
Cell Exhaustion

ABSTRACT The PD-1/PD-L pathway plays a major role in regulating T-cell exhaustion during chronic viral infections in animal models, as well as in humans, and blockade of this pathway can revive exhausted CD8+ T cells. We examined the expression of PD-1 and its ligands, PD-L1 and PD-L2, in multiple tissues during the course of chronic viral infection and determined how the amount of PD-1 expressed, as well as the anatomical location, influenced the function of exhausted CD8 T cells. The amount of PD-1 on exhausted CD8 T cells from different anatomical locations did not always correlate with infectious virus but did reflect viral antigen in some tissues. Moreover, lower expression of PD-L1 in some locations, such as the bone marrow, favored the survival of PD-1Hi exhausted CD8 T cells, suggesting that some anatomical sites might provide a survival niche for subpopulations of exhausted CD8 T cells. Tissue-specific differences in the function of exhausted CD8 T cells were also observed. However, while cytokine production did not strictly correlate with the amount of PD-1 expressed by exhausted CD8 T cells from different tissues, the ability to degranulate and kill were tightly linked to PD-1 expression regardless of the anatomical location. These observations have implications for human chronic infections and for therapeutic interventions based on blockade of the PD-1 pathway.

scholarly journals Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and function

2021 ◽  
Author(s):  
Elsa Brunet-Ratnasingham ◽  
Antigoni Morou ◽  
Mathieu Dube ◽  
Julia Niessl ◽  
Amy E. Baxter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Immune Checkpoints ◽  
Chronic Infections ◽  
Cell Functions ◽  
Art Initiation ◽  
Specific Regulation ◽  
And Function

Background: Antigen-specific T cell impairment is observed in chronic infections. CD4+ T cells are diverse in phenotype and function; how their different lineages are impacted by inhibitory immune checkpoints (IC) is unknown. Methods: We examined IC expression and function in HIV-specific CD4+ T cells of viremic individuals prior to ART initiation and persons with spontaneous or therapy-induced viral suppression. We investigated IC patterns associated with exhaustion-related transcription factors and chemokine receptors using cytokine-independent activation-induced marker assays. We determined effector functions representative of TFH, TH1 and TH17/TH22 using ultra-sensitive RNA flow cytometric fluorescence in situ hybridization (FISH), and their response to IC blockade. Findings: The dysfunction-related transcription factor TOX was elevated in HIV-specific CD4+ T cells of viremic patients, and its expression was associated with lineage differentiation. We observed a hierarchy of PD-1, TIGIT and CD200 expression associated with both infection status and effector profile. In vitro responsiveness to PD-L1 blockade varied with defined CD4+ T cell functions rather than IC expression levels: frequencies of cells with TH1- and TH17/TH22-, but not TFH-related functions, increased. Response to PD-L1 blockade was strongest in viremic participants and reduced after ART initiation. Interpretation: Our data highlight a polarization-specific regulation of IC expression and differing sensitivities of antigen-specific Thelper subsets to PD-1-mediated inhibition. This heterogeneity may direct ICB efficacy on CD4+ T cells in HIV infection.

scholarly journals A Combination of Anti-PD-L1 Treatment and Therapeutic Vaccination Facilitates Improved Retroviral Clearance via Reactivation of Highly Exhausted T Cells

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Torben Knuschke ◽  
Sebastian Kollenda ◽  
Christina Wenzek ◽  
Gennadiy Zelinskyy ◽  
Philine Steinbach ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Combination Therapy ◽  
Viral Infection ◽  
Viral Infections ◽  
T Cell Immunity ◽  
Chronic Viral Infection ◽  
Therapeutic Vaccination ◽  
Chronic Viral Infections ◽  
Cell Immunity

ABSTRACT PD-1-targeted therapies have shown modest antiviral effects in preclinical models of chronic viral infection. Thus, novel therapy protocols are necessary to enhance T cell immunity and viral control to overcome T cell dysfunction and immunosuppression. Here, we demonstrate that nanoparticle-based therapeutic vaccination improved PD-1-targeted therapy during chronic infection with Friend retrovirus (FV). Prevention of inhibitory signals by blocking PD-L1 in combination with therapeutic vaccination with nanoparticles containing the microbial compound CpG and a CD8+ T cell Gag epitope peptide synergistically enhanced functional virus-specific CD8+ T cell responses and improved viral clearance. We characterized the CD8+ T cell populations that were affected by this combination therapy, demonstrating that new effector cells were generated and that exhausted CD8+ T cells were reactivated at the same time. While CD8+ T cells with high PD-1 (PD-1hi) expression turned into a large population of granzyme B-expressing CD8+ T cells after combination therapy, CXCR5-expressing follicular cytotoxic CD8+ T cells also expanded to a high degree. Thus, our study describes a very efficient approach to enhance virus control and may help us to understand the mechanisms of combination immunotherapy reactivating CD8+ T cell immunity. A better understanding of CD8+ T cell immunity during combination therapy will be important for developing efficient checkpoint therapies against chronic viral infections and cancer. IMPORTANCE Despite significant efforts, vaccines are not yet available for every infectious pathogen, and the search for a protective approach to prevent the establishment of chronic infections, i.e., with HIV, continues. Immune checkpoint therapies targeting inhibitory receptors, such as PD-1, have shown impressive results against solid tumors. However, immune checkpoint therapies have not yet been licensed to treat chronic viral infections, since a blockade of inhibitory receptors alone provides only limited benefit, as demonstrated in preclinical models of chronic viral infection. Thus, there is a high interest in the development of potent combination immunotherapies. Here, we tested whether the combination of a PD-L1 blockade and therapeutic vaccination with functionalized nanoparticles is a potent therapy during chronic Friend retrovirus infection. We demonstrate that the combination therapy induced a synergistic reinvigoration of the exhausted virus-specific CD8+ T cell immunity. Taken together, our results provide further information on how to improve PD-1-targeted therapies during chronic viral infection and cancer.

CpG oligodeoxynucleotides allow for effective adoptive T-cell therapy in chronic retroviral infection

Blood ◽  
2006 ◽  
Vol 109 (7) ◽  
pp. 2982-2984 ◽  
Author(s):  
Anke R. M. Kraft ◽  
Frank Krux ◽  
Simone Schimmer ◽  
Claes Ohlen ◽  
Philip D. Greenberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Viral Infections ◽  
Adoptive T Cell Therapy ◽  
Chronic Infections ◽  
Retroviral Infection ◽  
T Cell Therapy ◽  
Viral Loads ◽  
Cpg Oligodeoxynucleotides

AbstractAdoptive T-cell therapy in cancer or chronic viral infections is often impeded by the development of functional impairment of the transferred cells. To overcome this therapeutic limitation we combined adoptive transfer of naive, virus-specific CD8+ T cells with immunostimulative CpG oligodeoxynucleotides (ODNs) in mice chronically infected with the Friend retrovirus. The CpG-ODN co-injection prevented the T cells from developing functional defects in IFNγ and granzyme production and degranulation of cytotoxic molecules. Thus, the transferred T cells were able to reduce chronic viral loads when combined with CpG-ODNs. This strategy provides a new approach for developing successful adoptive T-cell therapy against chronic infections.

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