Longitudinal Analysis of the Human T Cell Response during Acute Hantavirus Infection

Lindgren, Therese; Ahlm, Clas; Mohamed, Nik Abdullah Nik; Evander, Magnus; Ljunggren, Hans‐Gustaf; Björkström, Niklas K.

doi:10.1128/jvi.05548-11

Cited by 85 publications

(111 citation statements)

References 46 publications

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“…The dynamic changes in the CD8 low CD100 Ϫ T cell subset are in accordance with the theoretical pattern of the effector CD8 T cell antiviral response. Lindgren et al (30) found that there are high numbers of Ki67 ϩ CD38 ϩ HLA-DR ϩ effector CD8 T cells among the PBMCs of patients during the early phase after Puumala virus infection, and this subset subsequently contracted in parallel with a decrease in viral load, which is also consistent with our results. In our study, PD-1 was found to be consistently and highly expressed on the CD8 low CD100 Ϫ T cell subset during the disease course, which may represent the possibility that the apparent decrease in the CD8 low CD100 Ϫ T cell number in the late phase of the disease may be regulated by the PD-1 pathway.…”

Section: Cd8supporting

confidence: 82%

CD8^lowCD100⁻T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection

Liu

Yusi

et al. 2015

J Virol

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Hantaan virus (HTNV) infection can cause a severe lethal hemorrhagic fever with renal syndrome (HFRS) in humans. CD8؉ T cells play a critical role in combating HTNV infections. However, the contributions of different CD8 ؉ T cell subsets to the immune response against viral infection are poorly understood. Here, we identified a novel subset of CD8 CD8 T cells play a critical role in combating viral infections. Dramatic cellular changes occur as T cells transition through the following three characteristic phases of an antiviral response: initial activation and expansion, the death phase, and the formation of memory T cells. However, many aspects of these activation and differentiation processes are inadequately understood, particularly in humans. There are several important cell surface molecules that regulate the interactions between immune cells and, moreover, characterize cell differentiation and activation status.Sema4D, also called CD100, was the first immune semaphorin discovered (1) and is involved in several aspects of both humoral and cellular immunity (2-6). CD100 exists in both a membranebound form and a soluble form. Membrane-associated CD100 is expressed preferentially on T cells and weakly on B cells and antigen-presenting cells (APCs) (2, 7). CD72, the receptor for CD100, is expressed primarily on immune system cells and is present on the surface of most APCs and B cells. Interaction between CD72 and CD100 leads to dendritic cell (DC) maturation and cytokine production and enhances B cell activation (7).Because of the involvement of CD100 in the immune response, we hypothesized that CD100 may play an important role in the antiviral CD8 T cell response. However, there is limited information available regarding the role of CD100 in infectious diseases. Eriksson et al. (8) investigated the effects of HIV-1 infection on CD100 expression in T cells, and they observed that a subset of CD8 ϩ T cells lacking membrane-associated CD100 showed decreased functional capacity. Their findings suggested that loss of CD100 expression would most likely lead to dysfunctional immunity in HIV-1 infection. It is well accepted that there are many differences between acute infections and chronic infections. Acute infections usually result in effective antiviral immune responses, while chronic infections are often associated with suboptimal T cell function. Furthermore, HIV infects CD4 ϩ T cells and B cells and has profound pathological effects on the immune system, further confounding the interpretation of T cell dynamics following the acute phase. Therefore, it is important to investigate the functional role of CD100 in the CD8 antiviral response in acute infections.

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Section: Cd8supporting

confidence: 82%

CD8^lowCD100⁻T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection

Liu

Yusi

et al. 2015

J Virol

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“…Initial studies focused on determining the frequency of activated T and B cells using phenotypic markers that have previously been defined in humans following infection or vaccination (16)(17)(18)(19). CD4 and CD8 T cells were analyzed for their coexpression of the activation markers HLA-DR and CD38.…”

Section: Significancementioning

confidence: 99%

Human Ebola virus infection results in substantial immune activation

McElroy

Akondy

Davis

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

271

311

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Four Ebola patients received care at Emory University Hospital, presenting a unique opportunity to examine the cellular immune responses during acute Ebola virus infection. We found striking activation of both B and T cells in all four patients. Plasmablast frequencies were 10-50% of B cells, compared with less than 1% in healthy individuals. Many of these proliferating plasmablasts were IgG-positive, and this finding coincided with the presence of Ebola virus-specific IgG in the serum. Activated CD4 T cells ranged from 5 to 30%, compared with 1-2% in healthy controls. The most pronounced responses were seen in CD8 T cells, with over 50% of the CD8 T cells expressing markers of activation and proliferation. Taken together, these results suggest that all four patients developed robust immune responses during the acute phase of Ebola virus infection, a finding that would not have been predicted based on our current assumptions about the highly immunosuppressive nature of Ebola virus. Also, quite surprisingly, we found sustained immune activation after the virus was cleared from the plasma, observed most strikingly in the persistence of activated CD8 T cells, even 1 mo after the patients' discharge from the hospital. These results suggest continued antigen stimulation after resolution of the disease. From these convalescent time points, we identified CD4 and CD8 T-cell responses to several Ebola virus proteins, most notably the viral nucleoprotein. Knowledge of the viral proteins targeted by T cells during natural infection should be useful in designing vaccines against Ebola virus.Ebola infection | human immune response | immune activation | plasmablasts | T cells

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“…In accordance, hantaviruses trigger an unusually potent reaction of CD8 + T lymphocytes, that is devoid of regulatory T cells, and still detectable years after resolution [11][12][13][14]. Human CD8 + T cells are stimulated by HLA class I (HLA-I) molecules that present antigen-derived peptides.…”

Section: Introductionmentioning

confidence: 99%

Hantaviral mechanisms driving HLA class I antigen presentation require both RIG‐I and TRIF

et al. 2013

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Hantaviruses are emerging human pathogens. They induce an unusually strong antiviral response of human HLA class I (HLA-I) restricted CD8 + T cells that may contribute to tissue damage and hantavirus-associated disease. In this study, we analyzed possible hantaviral mechanisms that enhance the HLA-I antigen presentation machinery. Upon hantavirus infection of various human and primate cell lines, we observed transactivation of promoters controlling classical HLA molecules. Hantavirus-induced HLA-I upregulation required proteasomal activity and was associated with increased TAP expression. Intriguingly, human DCs acquired the capacity to cross-present antigen upon hantavirus infection. Furthermore, knockdown of TIR domain containing adaptor inducing IFN-β or retinoic acid inducible gene I abolished hantavirus-driven HLA-I induction. In contrast, MyD88-dependent viral sensors were not involved in HLA-I induction. Our results show that hantaviruses strongly boost the HLA-I antigen presentation machinery by mechanisms that are dependent on both retinoic acid inducible gene I and TIR domain containing adaptor inducing IFN-β.Keywords: Antigen presentation/processing · Cross-presentation/priming · Immunopathology · Infectious diseases · Innate immunity IntroductionRapidly changing ecosystems and climate facilitate the emergence of human infections with hantaviruses [1][2][3]. In Germany, increasing numbers of hantavirus-associated disease cases have been observed [4]. The enhanced health hazard emanating from pathogenic hantavirus species has been recognized by the German National Health Institute, which has recently reprioritized infecCorrespondence: Prof. Günther Schönrich e-mail: guenther.schoenrich@charite.de tious pathogens and placed hantaviruses in the highest priority group [5].Hantaviruses belong to the family Bunyaviridae and have segmented genomes [6]. The three viral RNA segments code for a nucleoprotein (N), two glycoproteins (Gn and Gc), and a RNA-dependent RNA polymerase. Hantaviruses are transmitted to humans by inhalation of virus-containing aerosols that are derived from the excreta of hantavirus-infected rodents. These natural reservoir hosts remain asymptomatic, although they are persistently infected. In striking contrast, hantaviruses are eliminated in humans at the cost of severe symptoms such as pulmonary or renal failure. Currently, no suitable vaccines or therapeutics are C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 2566-2576 Antigen processing 2567 available for prevention or treatment of human hantavirus infections [7,8].Hantaviruses are not directly cytopathic for infected cells, suggesting that the antiviral immune response itself causes hantavirus-associated syndromes [9,10]. In accordance, hantaviruses trigger an unusually potent reaction of CD8 + T lymphocytes, that is devoid of regulatory T cells, and still detectable years after resolution [11][12][13][14]. Human CD8 + T cells are stimulated by HLA class I (HLA-I) molecules that prese...

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Longitudinal Analysis of the Human T Cell Response during Acute Hantavirus Infection

Cited by 85 publications

References 46 publications

CD8^lowCD100⁻T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection

CD8^lowCD100⁻T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection

Human Ebola virus infection results in substantial immune activation

Hantaviral mechanisms driving HLA class I antigen presentation require both RIG‐I and TRIF

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Longitudinal Analysis of the Human T Cell Response during Acute Hantavirus Infection

Cited by 85 publications

References 46 publications

CD8lowCD100−T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection

CD8lowCD100−T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection

Human Ebola virus infection results in substantial immune activation

Hantaviral mechanisms driving HLA class I antigen presentation require both RIG‐I and TRIF

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CD8^lowCD100⁻T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection

CD8^lowCD100⁻T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection