In vitro generated human memory‐like T cells are CD95 type II cells and resistant towards CD95‐mediated apoptosis

Abstract

An adaptive immune response implies expansion of activated T cells and subsequent elimination to maintain homeostasis in a process called activation-induced cell death. Some cells, however, differentiate into memory cells and ensure a strong secondary immune response. To analyze the apoptosis phenotype of memory T cells on a cellular and molecular level, we have established an in vitro model of T cell activation and generation of cells phenotypically and functionally similar to memory cells. These longterm cultured T cells show a CD95-resistant phenotype, although they are still sensitive towards TCR/CD3-mediated apoptosis. Biochemical analysis revealed that these cells shift from CD95 type I (direct signaling from the receptor) during the effector phase to CD95 type II cells (dependent on the mitochondrial amplification loop). Moreover, their mitochondria are protected, probably due to high expression levels of Bcl-x L and Bcl-2. Thus, our data suggest a mechanism how memory T cells acquire resistance towards bystander cell death via the CD95 system.

Interleukin 7 Up-regulates CD95 Protein on CD4+ T Cells by Affecting mRNA Alternative Splicing

“…These data are consistent with previous understandings that memory CD4 ϩ T cells are CD95 type ⌱⌱ cells and are resistant to CD95-mediated apoptosis (31)(32)(33). Thus, memory CD4 ϩ T cells can achieve homeostatic proliferation with the protection of IL-7 and acquire CD95 resistance toward bystander cell death during HIV-1 infection or antigen restimulation.…”

“…ϩ T lymphocyte subsets including long-lived memory cells such as central memory T cells and stem cell-like memory T cells, CD95 ϩ memory cells are most likely resistant to CD95-mediated apoptosis (31)(32)(33). Peripheral T cells primed with high IL-7 doses have been characterized by an increased sensitivity to CD95-mediated proliferation as well as apoptosis (34).…”

Renal Cell Carcinoma Tumors Induce T Cell Apoptosis through Receptor-Dependent and Receptor-Independent Pathways

“…In these cells it is likely that, once recruited to amplify receptordependent apoptosis, mitochondria are fully integrated into the process, and unable to participate any further by additional, direct, receptor-independent insults. In fact, the finding that treatment with rFasL plus gangliosides did have an additive effect on MPT in primary T cells supports the notion that, unlike the type II Jurkat cells used in these studies, primary, activated T lymphocytes are type I cells (52), which can be killed by RCC tumor cells through both apoptotic pathways simultaneously. Indeed, because RCC tumor cells are heterogeneous with respect to their elaboration of TNF, gangliosides (29), and FasL (7), it is likely that they can initiate the apoptosis of contiguous T lymphocytes through either the extrinsic or intrinsic pathways, or both, depending on the levels and which proapoptotic molecule(s) the tumor cells are synthesizing.…”

Down-Regulation of Mcl-1 by Small Interfering RNA Sensitizes Resistant Melanoma Cells to Fas-Mediated Apoptosis

“…The role of Bcl-2 and Bcl-xL in the regulation of death receptor -induced and drug-induced apoptosis has been established in various cell types (28,50,51). A predominant role of Mcl-1 in the regulation of Fas apoptosis has recently been described in leukemia cells (52,53) and in human hepatocytes (54).…”