First analysis of human herpesvirus 6T-cell responses: Specific boosting after HHV6 reactivation in stem cell transplantation recipients

Pagter, Anne P J de; Boelens, Jaap Jan; Scherrenburg, J.; Blank, T. Vroom-de; Tesselaar, Kiki; Nanlohy, Nening M.; Sanders, Elisabeth A. M.; Schuurman, Rob; Baarle, Debbie van

doi:10.1016/j.clim.2012.06.006

Cited by 11 publications

(5 citation statements)

References 33 publications

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“…1C). Such an expansion and contraction pattern for CD4 ϩ T cells was previously observed in reconstitution under viral pressure (30). Of note, while the total numbers of CD4 ϩ T cells were comparable during the first 90 days after CBT (Fig.…”

Section: Cd4supporting

confidence: 80%

Cognate CD4 T-Cell Licensing of Dendritic Cells Heralds Anti-Cytomegalovirus CD8 T-Cell Immunity after Human Allogeneic Umbilical Cord Blood Transplantation

Flinsenberg

Spel

Jansen

et al. 2015

J Virol

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Reactivation of human cytomegalovirus (CMV) is hazardous to patients undergoing allogeneic cord blood transplantation (CBT), T-cell-mediated immunity and fight off viral reactivation in CBT patients. IMPORTANCE Survival rates after stem cell transplantation are lowered by 25% when patients undergo reactivation of cytomegalovirus (CMV) that they harbor. Immune protection against CMV is mostly executed by white blood cells called killer T cells. We here show that for generation of optimally protective killer T-cell responses that respond to CMV, the early elicitation of help from a second branch of CMV-directed T cells, called helper T cells, is required.C ytomegalovirus (CMV)-seropositive patients who are immunocompromised are at increased risk for developing potentially life-threatening CMV reactivation. Especially after allogeneic cord blood (CB) transplantation (CBT), the first weeks of immune reconstitution are hazardous for developing CMV reactivation, which is associated with decreased survival rates (1, 2). Antiviral treatment can reduce CMV viremia, but effective viral control requires induction of CMV-directed immunity by T lymphocytes. In particular, CD8 ϩ cytotoxic T lymphocytes (CTLs) fulfill a predominant role in protection against CMV disease (2-4). Therefore, strategies that increase early CMV-specific adaptive immune responses after transplantation are currently being explored, which could ultimately help to establish full clearance of, and long-term immunological memory against, CMV. In the human setting, cell-based therapy is being explored, geared toward dendritic cell (DC)-mediated activation of CTLs (5, 6). The elicitation of antigen-specific CTL immunity was in mouse models shown to require cognate CD4 ϩ T-cell licensing (7-10). Furthermore, priming of naive CD8 ϩ T cells requires both the CD4 ϩ T-helper cells and CD8 ϩ T cells to recognize antigen on the same antigen-presenting cell (5,11,12). Such CD4 ϩ T-cell help can involve CD40 ligand (CD40L) binding to CD40 on DCs (9,13,14). For humans, a requirement for CD4 CMV-specific CD4ϩ T-cell clones are present in the healthy population, suggesting a role for antigen-specific CD4 ϩ T cells in immunity against CMV, as 50 to 80% of adults experience CMV infection in their lifetime (6,15). Moreover, effective control of CMV infection was attained in patients when CMV-specific T cells, of which 77% were CD4 ϩ T cells, were infused (16). Further, human DCs loaded with both HLA class I and II/peptide complexes were more effective at generating antigen-specific CTL responses than were those loaded with solely major histocompatibility complex (MHC) class I/peptide complexes (17). In a different setting, not only the absence of antigen-specific CTLs but also the absence of specific CD4 ϩ T-helper cells resulted in higher

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Section: Cd4supporting

confidence: 80%

Cognate CD4 T-Cell Licensing of Dendritic Cells Heralds Anti-Cytomegalovirus CD8 T-Cell Immunity after Human Allogeneic Umbilical Cord Blood Transplantation

Flinsenberg

Spel

Jansen

et al. 2015

J Virol

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“…In pediatric hematopoietic cell transplant (HCT) patients, increased proportions of perforin-expressing CD8+ T cells have been temporally associated with HHV-6 clearance ( 30 ). HHV-6-specific CD8+ T cells with proliferative capacity were more readily detectable in patients after viral reactivation but not in those without ( 31 ). Moreover, MRV is lethal to CD8 knockout mice but not to wild-type mice ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Advances in the Characterization of the T-Cell Response to Human Herpesvirus-6

2018

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Human herpesvirus (HHV) 6 is thought to remain clinically latent in most individuals after primary infection and to reactivate to cause disease in persons with severe immunosuppression. In allogeneic hematopoietic stem cell transplant recipients, reactivation of HHV-6 species B is a considerable cause of morbidity and mortality. HHV-6B reactivation is the most frequent cause of infectious meningoencephalitis in this setting and has been associated with a variety of other complications such as graft rejection and acute graft versus host disease. This has inspired efforts to develop HHV-6-targeted immunotherapies. Basic knowledge of HHV-6-specific adaptive immunity is crucial for these endeavors, but remains incomplete. Many studies have focused on specific HHV-6 antigens extrapolated from research on human cytomegalovirus, a genetically related betaherpesvirus. Challenges to the study of HHV-6-specific T-cell immunity include the very low frequency of HHV-6-specific memory T cells in chronically infected humans, the large genome size of HHV-6, and the lack of an animal model. This review will focus on emerging techniques and methodological improvements that are beginning to overcome these barriers. Population-prevalent antigens are now becoming clear for the CD4+ T-cell response, while definition and ranking of CD8+ T-cell antigens and epitopes is at an earlier stage. This review will discuss current knowledge of the T-cell response to HHV-6, new research approaches, and translation to clinical practice.

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“…Responding T cells, measured as the number of IFN-γ producing cells, are present at low frequency (on the order of a few cells per 1000 (or <0.2%) [12,39,40], which contrasts sharply with the stronger responses that are observed for HCMV (up to 4%) [41]. T cell responses have been reported to be higher in HSCT patients [42], but few studies have focused on this population. Despite the low frequency of responding T cells in healthy adults, strong CD4+ and CD8+ T cell proliferative responses are observed [43–45], primarily restricted to memory cells.…”

Section: T Cell Responsesmentioning

confidence: 99%

“…However, as indicated by the authors, the clinical trial did not have enough participants to support a claim that reduction in virus levels was a result of infused of T cells rather than other host or viral factors. The T cell population transferred was highly enriched in CD4+ T cells with a minor component of CD8+ T cells, which may have been beneficial since allo-specific disease has been associated with higher frequency of HHV-6-specific CD8+ T cells [42]. …”

Section: Autologous Immune Enhancement Therapymentioning

confidence: 99%

Immune response to HHV-6 and implications for immunotherapy

Becerra

Gibson

Stern

et al. 2014

Current Opinion in Virology

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Most adults remain chronically infected with HHV-6 after resolution of a primary infection in childhood, with the latent virus held in check by the immune system. Iatrogenic immunosuppression following solid organ transplantation (SOT) or hematopoetic stem cell transplantation (HSCT) can allow latent viruses to reactivate. HHV-6 reactivation has been associated with increased morbidity, graft rejection, and neurological complications posttransplantation. Recent work has identified HHV-6 antigens that are targeted by the CD4+ and CD8+ T cell response in chronically infected adults. T cell populations recognizing these targets can be expanded in vitro and are being developed for use in autologous immunotherapy to control post-transplantation HHV-6 reaction.

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First analysis of human herpesvirus 6T-cell responses: Specific boosting after HHV6 reactivation in stem cell transplantation recipients

Cited by 11 publications

References 33 publications

Cognate CD4 T-Cell Licensing of Dendritic Cells Heralds Anti-Cytomegalovirus CD8 T-Cell Immunity after Human Allogeneic Umbilical Cord Blood Transplantation

Cognate CD4 T-Cell Licensing of Dendritic Cells Heralds Anti-Cytomegalovirus CD8 T-Cell Immunity after Human Allogeneic Umbilical Cord Blood Transplantation

Advances in the Characterization of the T-Cell Response to Human Herpesvirus-6

Immune response to HHV-6 and implications for immunotherapy

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