Human cytomegalovirus (CMV) infection or reactivation is a frequent cause of morbidity and mortality in immunocompromised individuals, such as solid organ transplant recipients. The adoptive antiviral T-cell therapy is a novel therapeutic approach to regenerate immune competence in those patients to effectively combat viral infections. Our group could recently accentuate the signaling requirements for the generation of antigen-specific central memory T cells (TCM), which are associated with long-lasting protection to viruses and tumors. Targeting the interleukin-2-receptor (IL-2R) by partial mTOR inhibition or blocking IL-2R-alpha enriches human CD4+/CD8+ TCM within the virus-specific T-cell product. We herein showed that partial IL-2 and IL-7 signaling is required to enable TCM expansion. However, a systematic examination of common gamma chain cytokines indispensable for in vitro expansion of the T cells still needs to be elucidated. Moreover, recent GMP-compliant protocols apply solely IL-2 for the T-cell expansion. In the present study, we evaluated the impact of the growth promoting gamma chain cytokines during the expansion phase on the virus-specific cytotoxic T lymphocytes. We could identify the combination of the cytokines IL- 2, IL-7 and IL-15 enriches central memory T-cells as defined by a significant higher proportion and absolute number of CCR7+/CD62L+ (CD45RA-) T cells. The generated T-cell lines showed effector cytokine secretion, like IFNΓ and TNFΑ. We could moreover define the narrow range of the cytokine concentration regulating distinct memory T cell subsets. In this work we could highlight the enormous differential impact of growth promoting gamma chain cytokines during the expansion phase on the virus-specific cytotoxic T-cells (CTL) for the generation of antigen-specific TCM. This study possesses important implications for the CTL generation and the subsequent selection for in vivo clinical use of adoptive immunotherapy to improve long-lasting effects in transplant patient suffering from severe CMV disease.

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