The role of CD4+ T cells in BKV-specific T cell immunity |
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Authors: | B. J. D. Weist M. Schmueck H. Fuehrer A. Sattler P. Reinke N. Babel |
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Affiliation: | 1. Department of Nephrology, Charité University Medicine, Berlin, Germany 2. Berlin Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany 3. Institute of Medical Immunology, Charité University Medicine, Berlin, Germany
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Abstract: | Reactivation of polyomavirus BK (BKV) infection represents a severe complication in kidney transplant (KTX) patients. We previously reported an association between a declining BK viral load and the reconstitution of CD4+ T cell BKV-specific immunity in patients following kidney transplantation. However, the specific contribution of CD4+ T cells in the regulation of BKV-replication is unknown. Nevertheless, in vitro enrichment of BKV-specific T cells and subsequent adoptive T cell transfer may improve the restoration of immune competence in KTX patients with BKV infection. To date, strategies to capture human BKV-specific T cells with the ensuing expansion to clinically useful numbers are lacking. Here, we demonstrated a comprehensive flow cytometric analysis of the BKV-specific T cell response that permits access to the majority of T cells specific for immunodominant BKV antigens. A full-spectrum evaluation of the BKV-specific T cell response was performed by stimulating peripheral blood mononuclear cells (PBMC) with a mixture of BKV immunodominant peptide pools at varying concentrations and measuring activation marker expression and cytokine secretion. We also examined the effects of co-stimulation and PBMC resting time prior to activation. We defined the narrow range of stimulation conditions that permit the capture and expansion of functional BKV-specific T cell lines. The generated BKV-specific T cell lines showed the highest specificity and functionality when the T cells were captured according to IFNγ-secretion. This study highlights the multifunctional and cytolytic BKV-specific CD4+ T cells as a dominant population within the generated T cell product. This method offers a novel approach for the generation of BKV-specific T cell lines for adoptive immunotherapy and underscores the critical role of CD4+ T cells in the clearance of BKV. |
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