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Trans-vivo Delayed Type Hypersensitivity Assay for Antigen Specific Regulation
Published on: May 2, 2013
Missing HLA class I expression on Daudi cells unveils cytotoxic and proliferative responses of human gammadelta T
Simon Rothenfusser1, Armin Buchwald, Sylvia Kock
1Division of Clinical Pharmacology, Department of Medicine, University of Munich, Germany.
Insights
Human gammadelta T cells target cells lacking beta(2)-microglobulin. Restoring HLA class I on these cells inhibits gammadelta T cell responses, revealing TCR specificity for HLA class I loss.
Area of Science:
- Immunology
- Cellular Biology
- T-cell Receptor Signaling
Background:
- Human gammadelta T lymphocytes expressing Vgamma9/Vdelta2 T-cell receptors (TCRs) recognize non-peptidic antigens.
- These cells are implicated in recognizing beta(2)-microglobulin-deficient Daudi cells.
- Inhibitory natural killer cell receptors for HLA class I modulate gammadelta T-cell responses.
Purpose of the Study:
- To investigate the role of beta(2)-microglobulin and HLA class I in the recognition of Daudi cells by Vgamma9/Vdelta2 T cells.
- To elucidate the specificity of Vgamma9/Vdelta2 T cells in targeting cells with altered HLA class I expression.
Main Methods:
- Transfection of human beta(2)-microglobulin cDNA into Daudi cells.
- Assessment of cytotoxic and proliferative responses of Vgamma9/Vdelta2 T cells.
- Expression of HLA class I molecules (A, B, C) with mouse beta(2)-microglobulin in Daudi cells.
- Cloning and transfer of individual HLA class I molecules into HLA class I-deficient cell lines (221 and C1R).
Main Results:
- Transfection of beta(2)-microglobulin into Daudi cells markedly inhibited Vgamma9/Vdelta2 T-cell responses, confirming antigen recognition is linked to beta(2)-microglobulin loss.
- Daudi cells expressing HLA class I with mouse beta(2)-microglobulin were recognized similarly to parental cells, indicating proper HLA class I conformation is crucial for NK cell receptor binding.
- Individual HLA class I alleles differentially inhibited cytotoxicity mediated by gammadelta T-cell clones, highlighting allele-specific interactions.
Conclusions:
- The "innate" specificity of human Vgamma9/Vdelta2 T-lymphocytes for Daudi cells is uncovered by the loss of beta(2)-microglobulin.
- Proper conformation of HLA class I molecules is required for recognition by natural killer cell receptors.
- Human Vgamma9/Vdelta2 T cells function as killer cells targeting cells with lost HLA class I expression, with specificity dictated by the Vgamma9/Vdelta2 TCR.
Abstract:
The major subset of human blood gammadelta T lymphocytes expresses the variable-region genes Vgamma9 and Vdelta2. These cells recognize non-peptidic phosphoantigens that are present in some microbial extracts, as well as the beta(2)-microglobulin-deficient Burkitt's lymphoma Daudi. Most cytotoxic human Vgamma9/Vdelta2 T cells express inhibitory natural killer cell receptors for HLA class I that downmodulate the responses of the gammadelta T lymphocytes against HLA class I expressing cells. In this study we show that transfection of the human beta(2)-microglobulin cDNA into Daudi cells markedly inhibits the cytotoxic and proliferative responses of human Vgamma9/Vdelta2 T cells. This provides direct evidence that the "innate" specificity of human Vgamma9/Vdelta2 T-lymphocytes for Daudi cells is uncovered by the loss of beta(2)m by Daudi. However, Daudi cells that express HLA class I in association with mouse beta(2)m at the cell surface are recognized by human Vgamma9/Vdelta2 T cells close to the same degree as the parental HLA class I deficient Daudi cell line. Thus, proper conformation of the HLA class I molecules is required for binding to natural killer cell receptors. Cloning of the HLA class I A, B, and C molecules of Daudi cells and transfer of the individual HLA class I molecules of Daudi cells into the HLA class I deficient recipient cell lines.221 and C1R demonstrate that for some human gammadelta T-cell clones cytolysis can be entirely inhibited by single HLA class I alleles while for other clones single HLA class I alleles only partially inhibit cytotoxicity. Thus, most human Vgamma9/Vdelta2 T cells represent a population of killer cells that evolved like NK cells to destroy target cells that have lost expression of individual HLA class I molecules but with a specificity that is determined by the Vgamma9/Vdelta2 TCR.
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