Abstract
Evidences are accumulating that CD4+ T cells can physiologically mediate antigen specific target cell lysis. By circumventing major histocompatibility complex (MHC)-restrictions through an engineered chimeric antigen receptor (CAR), CD4+ T cells lyse defined target cells as efficiently as do CD8+ T cells. However, the cytolytic capacity of redirected CD4+CD25− T cells, in comparison with CD4+CD25+ regulatory T (Treg) cells was so far not thoroughly defined. Treg cells require a strong CD28 signal together with CD3ζ for activation. We consequently used a CAR with combined CD28CD3ζ signalling for redirecting CD4+CD25− T cells and CD4+CD25+ Treg cells from the same donor. CAR redirected activation of these T cell subsets and induced a distinct cytokine pattern with high IL-10 and a lack of IL-2 release by Treg cells. Despite strong antigen-specific activation, CAR Treg cells produced only weak target cell lysis, whereas CD4+CD25− CAR T cells were potent killers. Cytolysis did not correlate with the target cell sensitivity to Fas/FasL mediated killing; CD4+CD25− T cells upregulated perforin and granzyme B upon CAR activation, whereas Treg cells did less. The different cytolytic capacities of CAR redirected conventional CD4+ cells and Treg cells imply their use for different purposes in cell therapy.
Highlights
T cells can be antigen- redirected by genetic engineering with a chimeric antigen receptor (CAR) that combines the advantages of antibody mediated target recognition with the induction of T cell effector functions [1]
+CD25− and CD4+CD25+ T cells were isolated from the peripheral blood of healthy donors procedures
T cells from the peripheral blood can efficiently be redirected for specific cytolysis by a CAR, which bypasses the major histocompatibility complex (MHC) class II restriction
Summary
T cells can be antigen- redirected by genetic engineering with a chimeric antigen receptor (CAR) that combines the advantages of antibody mediated target recognition with the induction of T cell effector functions [1]. CAR T cells execute a cellular response in a specific fashion, as indicated by cytokine release, T cell amplification and lysis of cognate target cells. Since the CAR circumvents the MHC (major histocompatibility complex) restriction, both CD8+ and CD4+ T cells can be activated through the same CAR. The recently described MHC class II-restricted CD4+ cytotoxic T cells (CD4+ CTLs) emerge during chronic viral infections [3,4] and during an anti-tumor response [5,6]
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