CD8+ T Lymphocyte Expansion, Proliferation and Activation in Dengue Fever

Matos, Andréia Manso de; Carvalho, Karina I.; Rosa, Daniela Santoro; Villas-Boas, Lucy Santos; Silva, Wanessa Cardoso da; Rodrigues, Célia Luiza de Lima; Oliveira, Olímpia M. N. P. F.; Levi, José Eduardo; Araújo, Evaldo Stanislau Affonso de; Pannuti, Cláudio Sérgio; Luna, Expedito; Kallas, Esper G.

doi:10.1371/journal.pntd.0003520

Cited by 23 publications

(27 citation statements)

References 40 publications

(42 reference statements)

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“…2A and B). Moreover, our results from India and Thailand are consistent with previous studies reporting expansion of HLA-DR + CD38 + and HLA-DR − CD38 + cells in dengue patients from Brazil (4) and Vietnam (6). The previous studies also suggested that the numbers of activated CD8 T cells were higher in dengue patients with severe disease.…”

Section: Resultssupporting

confidence: 92%

Characterization of Human CD8 T Cell Responses in Dengue Virus-Infected Patients from India

Chandele

Sewatanon

Gunisetty

et al. 2016

J Virol

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Epidemiological studies suggest that India has the largest number of dengue virus infection cases worldwide. However, there is minimal information about the immunological responses in these patients. CD8 T cells are important in dengue, because they have been implicated in both protection and immunopathology. Here, we provide a detailed analysis of HLA-DR+ CD38+ and HLA-DR− CD38+ effector CD8 T cell subsets in dengue patients from India and Thailand. Both CD8 T cell subsets expanded and expressed markers indicative of antigen-driven proliferation, tissue homing, and cytotoxic effector functions, with the HLA-DR+ CD38+ subset being the most striking in these effector qualities. The breadth of the dengue-specific CD8 T cell response was diverse, with NS3-specific cells being the most dominant. Interestingly, only a small fraction of these activated effector CD8 T cells produced gamma interferon (IFN-γ) when stimulated with dengue virus peptide pools. Transcriptomics revealed downregulation of key molecules involved in T cell receptor (TCR) signaling. Consistent with this, the majority of these CD8 T cells remained IFN-γ unresponsive even after TCR-dependent polyclonal stimulation (anti-CD3 plus anti-CD28) but produced IFN-γ by TCR-independent polyclonal stimulation (phorbol 12-myristate 13-acetate [PMA] plus ionomycin). Thus, the vast majority of these proliferating, highly differentiated effector CD8 T cells probably acquire TCR refractoriness at the time the patient is experiencing febrile illness that leads to IFN-γ unresponsiveness. Our studies open novel avenues for understanding the mechanisms that fine-tune the balance between CD8 T cell-mediated protective versus pathological effects in dengue.IMPORTANCE Dengue is becoming a global public health concern. Although CD8 T cells have been implicated both in protection and in the cytokine-mediated immunopathology of dengue, how the balance is maintained between these opposing functions remains unknown. We comprehensively characterized CD8 T cell subsets in dengue patients from India and Thailand and show that these cells expand massively and express phenotypes indicative of overwhelming antigenic stimulus and tissue homing/cytotoxic-effector functions but that a vast majority of them fail to produce IFN-γ in vitro. Interestingly, the cells were fully capable of producing the cytokine when stimulated in a T cell receptor (TCR)-independent manner but failed to do so in TCR-dependent stimulation. These results, together with transcriptomics, revealed that the vast majority of these CD8 T cells from dengue patients become cytokine unresponsive due to TCR signaling insufficiencies. These observations open novel avenues for understanding the mechanisms that fine-tune the balance between CD8-mediated protective versus pathological effects.

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Section: Resultssupporting

confidence: 92%

Characterization of Human CD8 T Cell Responses in Dengue Virus-Infected Patients from India

Chandele

Sewatanon

Gunisetty

et al. 2016

J Virol

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“…Previous reports have indicated that CD4 ϩ and CD8 ϩ T cells play a role in the control of DV infection, mostly due to T cell-dependent cytotoxicity against virus-infected cells (11,12). In support of this concept, CD8 ϩ T cell activation and proliferation are inversely correlated with dengue viremia and appear to occur late in the course of DV infection (13). In contrast, low-affinity anti-DV T cells, induced during secondary heterotypic infection, contribute to the high viral load and intense inflammatory cytokine secretion observed in severe dengue cases (14).…”

mentioning

confidence: 69%

“…In contrast, low-affinity anti-DV T cells, induced during secondary heterotypic infection, contribute to the high viral load and intense inflammatory cytokine secretion observed in severe dengue cases (14). Moreover, activated CD4 ϩ and CD8 ϩ T cells have previously been found to be associated with hemorrhagic disease (10,13,15). This suggests that while T cells may contribute to controlling DV replication, they could also be involved in the pathogenesis of the disease (3,16).…”

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confidence: 99%

Human T Lymphocytes Are Permissive for Dengue Virus Replication

Silveira

Wowk

Cataneo

et al. 2018

J Virol

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Dengue virus (DV) infection can cause either a self-limiting flu-like disease or a threatening hemorrhage that may evolve to shock and death. A variety of cell types, such as dendritic cells, monocytes, and B cells, can be infected by DV. However, despite the role of T lymphocytes in the control of DV replication, there remains a paucity of information on possible DV-T cell interactions during the disease course. In the present study, we have demonstrated that primary human naive CD4 and CD8 T cells are permissive for DV infection. Importantly, both T cell subtypes support viral replication and secrete viable virus particles. DV infection triggers the activation of both CD4 and CD8 T lymphocytes, but preactivation of T cells reduces the susceptibility of T cells to DV infection. Interestingly, the cytotoxicity-inducing protein granzyme A is highly secreted by human CD4 but not CD8 T cells after exposure to DV Additionally, using annexin V and polycaspase assays, we have demonstrated that T lymphocytes, in contrast to monocytes, are resistant to DV-induced apoptosis. Strikingly, both CD4 and CD8 T cells were found to be infected with DV in acutely infected dengue patients. Together, these results show that T cells are permissive for DV infection and, suggesting that this cell population may be a viral reservoir during the acute phase of the disease. Infection by dengue virus (DV) causes a flu-like disease that can evolve to severe hemorrhaging and death. T lymphocytes are important cells that regulate antibody secretion by B cells and trigger the death of infected cells. However, little is known about the direct interaction between DV and T lymphocytes. Here, we show that T lymphocytes from healthy donors are susceptible to infection by DV, leading to cell activation. Additionally, T cells seem to be resistant to DV-induced apoptosis, suggesting a potential role as a viral reservoir in humans. Finally, we show that both CD4 and CD8 T lymphocytes from acutely infected DV patients are infected by DV. Our results raise new questions about DV pathogenesis and vaccine development.

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“…In addition to our studies revealing an association between HLA-linked T cell responses and disease susceptibility (Weiskopf et al, 2013, Weiskopf et al, 2015b), an earlier study by a different group observed that the breadth and magnitude of the CD8 T cell response during secondary DENV infection was not significantly associated with disease severity (Simmons et al, 2005). Most recently, another group reported that the expansion of effector memory CD8 T cells during acute DENV infection correlated with reduced viremia (de Matos et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Protective Role of Cross-Reactive CD8 T Cells Against Dengue Virus Infection

et al. 2016

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Infection with one of the four dengue virus serotypes (DENV1-4) presumably leads to lifelong immunity against the infecting serotype but not against heterotypic reinfection, resulting in a greater risk of developing Dengue Hemorrhagic Fever/Dengue Shock Syndrome (DHF/DSS) during secondary infection. Both antibodies and T cell responses have been implicated in DHF/DSS pathogenesis. According to the T cell-based hypothesis termed “original antigenic sin,” secondary DENV infection is dominated by non-protective, cross-reactive T cells that elicit an aberrant immune response. The goal of our study was to compare the roles of serotype-specific and cross-reactive T cells in protection vs. pathogenesis during DENV infection in vivo. Specifically, we utilized IFN-α/βR−/− HLA*B0702 transgenic mice in the context of peptide vaccination with relevant human CD8 T cell epitopes. IFN-α/βR−/− HLA*B0702 transgenic mice were immunized with DENV serotype 2 (DENV2)-specific epitopes or variants found in any of the other three serotypes (DENV1, DENV3 or DENV4), followed by challenge with DENV. Although cross-reactive T cell responses were lower than responses elicited by serotype-specific T cells, immunization with either serotype-specific or variant peptide epitopes enhanced viral clearance, demonstrating that both serotype-specific and cross-reactive T cells can contribute to protection in vivo against DENV infection.

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CD8+ T Lymphocyte Expansion, Proliferation and Activation in Dengue Fever

Cited by 23 publications

References 40 publications

Characterization of Human CD8 T Cell Responses in Dengue Virus-Infected Patients from India

Characterization of Human CD8 T Cell Responses in Dengue Virus-Infected Patients from India

Human T Lymphocytes Are Permissive for Dengue Virus Replication

Protective Role of Cross-Reactive CD8 T Cells Against Dengue Virus Infection

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