EBV-Specific CD4+ T Cell Clones Exhibit Vigorous Allogeneic Responses

Landais, Elise; Morice, Alexis; Long, Heather M.; Haigh, Tracey A.; Charreau, Béatrice; Bonneville, Marc; Taylor, Graham S.; Houssaint, Elisabeth

doi:10.4049/jimmunol.177.3.1427

Cited by 31 publications

(25 citation statements)

References 41 publications

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“…56,57,63,64,84 Recent experiments have also shown that human CD4 T cell lines specific for CMV or EBV cross-react with allogeneic MHC class II. 85,86 In detailed studies of cross-reactivity during an acute infection of C57BL/6 mice (H2 b ), we showed that LCMV-specific CD8 T cells defined by MHC-tetramer staining produce IFN-␥ after in vitro stimulation with allogeneic cell lines but not with syngeneic cell lines (Figure 3). 24 This cross-reactivity was broad based in that a proportion of each of the four epitope-specific responses (GP33, GP276, NP205, and NP396) examined recognized H2 d antigens.…”

Section: Cross-reactivity Between Virusspecific T Cells and Alloantigensmentioning

confidence: 99%

Frontiers in Nephrology

Selin¹,

Brehm²

2007

Journal of the American Society of Nephrology

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Section: Cross-reactivity Between Virusspecific T Cells and Alloantigensmentioning

confidence: 99%

Frontiers in Nephrology

Selin¹,

Brehm²

2007

Journal of the American Society of Nephrology

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“…In all experiments, HLA-A2/GLC and HLA-B8/RAK tetrameric complex staining served as negative controls. The proliferation assays for EBV EBNA3A-specific T cell responses were repeated using 20 …”

Section: Proliferation Assays For Ebv Ebna3a-specific T Cell Responsesmentioning

confidence: 99%

“…A high level of cross-reactivity against allo-HLA molecules is therefore an essential feature of the virus-specific memory TCR (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). This allo-HLA cross-reactivity by virus-specific T cells can be reproducibly detected in vitro.…”

mentioning

confidence: 99%

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

D’Orsogna

Heuvel

Meer-Prins

et al. 2012

The Journal of Immunology

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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.

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“…This was probably due to T-cell alloresponse to the allo-MHC molecules other than the E7/HLA-DR15 T cells, likely acting on the tumor and its microenvironment, are responsible for the enhancement of the in vivo complex, because nonspecific CD4 + T cells may not have been completely excluded from the responders, chemotherapeutic antitumor activity (37), and indirect tumor-killing effects of IFN-γ are reported in human even after conducting careful enrichment, although there exists the possibility that the virus-specific T cells are tumor xenograft models (17). It is suggested that the allorestricted CD4 + T cells recognized tumor and cross-reactive to HLA class II mismatches (28,46). became activated to ultimately result in tumor rejection Tumor Rejection Effects of Allorestricted E7-Specific via complicated, presently incompletely defined mecha-CD4 + T cells in SiHa Cell-Challenged Nude Mice nisms, since the allorestricted CD4 + T cells showed TCR ligand-specific IFN-γ production (Fig.…”

Section: Specific Peptide/hla-dr15 Dimer Staining Assay and Ifn-γ Elimentioning

confidence: 99%

Tumor Rejection Effects of Allorestricted Tumor Peptide-Specific CD4⁺T Cells on Human Cervical Cancer Cell Xenograft in Nude Mice

et al. 2012

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Generation of tumor specific alloreactive CD4+ T cells is important to circumvent tumor tolerance. Here, we generate allorestricted peptide-specific CD4 + T cells by coculture of lymphocytes and autologous monocytes bearing allogeneic HLA-DR15 molecule associated with its restricted peptide. Binding of a dimeric HLA-DR15/IgG1-Fc fusion protein (the dimer) to HLA-DR15 negative (HLA-DR15-ve) monocytes made the monocytes coated with the allogeneic epitope. An increased proliferation of CD4 + T cells and induction of Th1 cells appeared after coculturing of HLA-DR15-ve lymphocytes and the autologous monocytes loaded with the dimer. The cocultural bulks showed an increased frequency of the specific dimer-stained CD4+ T cells and the expanded CD4 + T cells exhibited an elevated IFN-γ production in response to specific TCR ligand. Tumor rejection effects of the allorestricted E7-specific CD4 + T cells raised by the coculture were observed in nude mice challenged with human cervical cancer cell SiHa expressing both HLA-DR15 and E7 antigens, as the tumor avoidance and life span of the mice were improved after adoptive transfer of the CD4 + T cells. This study may help to develop strategies to separate graft-versus-leukemia or graft-versustumor reaction from graft-versus-host disease, and add to the pool of human high-avidity TCRs specific for tumor or virus antigens.Key words: Tumor rejection; Allorestricted; Tumor peptide specific; CD4 + T cell INTRODUCTIONIt has been observed that CD4 + but not CD8 + T cells are essential for allorejection (7,26), since CD4 + T cells are generally regarded as helper cells by facilitating T cells play a major role in allograft rejection and graft-versus-host disease (GVHD); both CD4 + and CD8 + other immune cells (12) and effector cells of graft rejection (47). It is well established that leukemia patients T cells are involved in the process (21)(22)(23)31). T-cell receptors (TCRs) are formed by antigenic peptide assocan benefit from graft-versus-leukemia reaction (GVLR) (9,54), and evidences of graft-versus-tumor reaction ciated with major histocompatibility complex (MHC) class I or class II molecule, which are recognized by (GVTR) have also been reported in many solid tumors (6,8,14), in which donor immune cells mount a response CD8 + and CD4 + T cells, respectively (21). Direct T-cell allorecognition is the principal player in vigorous against recipients' leukemia or tumor cells. Both CD4 + and CD8 + T cells are required for GVLR (5), although response to allogeneic cells that causes acute rejection (49). The structure basis for T-cell direct recognition has most studies focus on the role of CD8 + T cells in GVLR or GVTR and reveal CD8 + T cell is an effective means been actively investigated (10,26,41,53). Current belief in the field is that allogeneic T-cell responses, like syn- (24,43,45). Based on the importance of CD4 + T cells in both nominal and allogeneic responses, we propose geneic T-cell responses, are largely peptide specific, and that TCRs interact with allogeneic MHC in ...

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EBV-Specific CD4+ T Cell Clones Exhibit Vigorous Allogeneic Responses

Cited by 31 publications

References 41 publications

Frontiers in Nephrology

Frontiers in Nephrology

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

Tumor Rejection Effects of Allorestricted Tumor Peptide-Specific CD4⁺T Cells on Human Cervical Cancer Cell Xenograft in Nude Mice

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EBV-Specific CD4+ T Cell Clones Exhibit Vigorous Allogeneic Responses

Cited by 31 publications

References 41 publications

Frontiers in Nephrology

Frontiers in Nephrology

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

Tumor Rejection Effects of Allorestricted Tumor Peptide-Specific CD4+T Cells on Human Cervical Cancer Cell Xenograft in Nude Mice

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Tumor Rejection Effects of Allorestricted Tumor Peptide-Specific CD4⁺T Cells on Human Cervical Cancer Cell Xenograft in Nude Mice