Stimulation of Human EBV- and CMV-Specific Cytolytic Effector Function Using Allogeneic HLA Molecules

Abstract

Viral infection is a major cause of morbidity and mortality, and there are few therapeutic options available to augment a virus-specific T cell response. Although allo-HLA cross-reactivity from virus-specific memory T cells is common, it is unclear whether priming with specific allogeneic cells could conversely elicit a viral peptide/self-HLA restricted cytotoxic T cell response in humans. First, we used the previously described allo-HLA-B*44:02 cross-reactivity of EBV peptide/HLA-B8 restricted T cells, to determine whether allogeneic HLA stimulation can elicit a cytolytic immune response against EBV. HLA-B8+ HLA-B44− EBV-seropositive PBMCs were stimulated with either HLA-B*44:02+ or HLA-B*44:03+ mismatched irradiated PBMCs in a 7–10 d MLR. The allo-HLA stimulated responder cells were then evaluated for cytotoxicity using EBV peptide loaded autologous target cells and unloaded HLA-B8+ EBV LCL target cells. PBMCs from EBV-seropositive donors gained EBV-specific cytolytic effector function following specific allo-HLA stimulation. Finally, we also elicited cytolytic CMV-specific responses using specific allogeneic cell stimulation, to confirm that this technique can be used to elicit viral peptide/self-HLA restricted responses even from nonpublic TCR responses. Allogeneic cell stimulation used as a cell therapy may be a potential tool to augment an antiviral T cell response in patients with EBV or CMV infection.

Functionality testing of stem cell grafts to predict infectious complications after allogeneic hematopoietic stem cell transplantation

“…With respect to our data, this proposes that IL‐1β is also a master regulator for activation and proliferation of protective antigen‐specific T‐cells in an allogeneic transplantation setting. Additionally, allogeneic stimulation per se has been shown to be beneficial in an in vitro study demonstrating that stimulation with viral antigens, binding EBV‐ and CMV‐ specific T‐cells, in combination with allogeneic stimulation increased the number of antigen‐specific T‐cells and their effector function .…”

Heterologous Immunity of Virus-Specific T Cells Leading to Alloreactivity: Possible Implications for Solid Organ Transplantation

“…The classical model of heterologous immunity clearly illustrates the presence of both private and public TCRs for a single viral specificity. HLA-B8-restricted EBV/FLR-specific memory CD8+ T cells cross-react with HLA-B*4402, -B*44:05 and -B*55:01 but not with HLA-B*44:03 [48,49]. While the TCR involved in cross-reactivity with HLA-B*4402, -B*44:05 has been shown to be public (LC13) being expressed in multiple HLA-B8+ individuals with a history of EBV infection [50,51], cross-reactivity with HLA-B*55:01 has been shown to be mediated by a private TCR [27,51].…”

Emerging novel and antimicrobial-resistant respiratory tract infections: new drug development and therapeutic options

“…87 They change gene expression by inhibiting translation, disrupting RNA secondary structure, and interfering with pre-mRNA splicing. 88 The usefulness of phosphorodiamidate morpho lino oligomers coupled to argininerich cell-penetrating peptides has been repeatedly demonstrated against bacterial pathogens 89 and could be a viable option for any microbial gene of interest.…”