Programmed Cell Death 1 and Helios Distinguish TCR-αβ+ Double-Negative (CD4−CD8−) T Cells That Derive from Self-Reactive CD8 T Cells

Abstract

TCR-αβ+ double negative (DN; CD4-CD8-) T cells represent a poorly understood cellular subset suggested to contribute to the pathogenesis of the autoimmune disease systemic lupus erythematosus. DN T cells have been proposed to derive from CD8+ cells. However, the conditions that govern the loss of CD8 expression after antigen encounter are unknown. Here we tracked the fate of CD8 T cells from transgenic TCR mice exposed to their cognate antigens as self or in the context of infection. We demonstrate that CD8 T cells lose CD8 expression and become DN only when cognate antigen is sensed as self. This process is restricted to tissues where the antigen is present. We also show that DN T cells derived from self-reactive CD8 cells express the inhibitory molecules PD-1 and Helios. These molecules identify a subset of DN T cells in normal mice. A similar population expands when CD8 T cells from repertoires enriched in self-reactive cells (Aire-deficient) are transferred into cognate hosts. Collectively, our data suggest that a subset of DN T cells, identified by the expression of PD-1 and Helios, represent self-reactive cells. Our results provide an explanation for the origin of DN T cells and introduce CD8 loss as a process associated to self-antigen encounter.

T cells in Systemic Lupus Erythematosus

“…Such therapies may increase susceptibility to infections, the highest cause of death in SLE, so careful consideration will be required [1]. In addition, PD-1 plays a role in the generation of DN T cells from autoreactive T cells [11], which plays a pathogenic role in SLE. The conversion of CD8 T cells into double-negative T cells, as well as PD-1 expression, could explain the loss of cytotoxicity against viruses in SLE CD8 T cells.…”

Pro‐inflammatory self‐reactive T cells are found within murine TCR‐αβ+CD4−CD8−PD‐1+ cells

“…Previous studies have suggested that under certain conditions, CD8 + T cells may lose CD8 expression and become DN . Moreover, we have previously shown that self‐reactive CD8 + T cells lose CD8 expression after recognition of cognate self‐antigen and become DN T cells, supporting the concept that CD8 downregulation may represent an active mechanism of peripheral tolerance . Here, we analyze DN T cells in normal, unmanipulated mice and show that programmed cell death 1 (PD‐1) expression identifies a subset of DN T cells that displays activation markers, produces pro‐inflammatory cytokines, and, importantly, exhibits evidence of TCR‐mediated activation.…”

“…Self‐reactive CD8 + T cells become inactivated upon exposure to cognate self‐antigen. During this process, they downregulate CD8 and upregulate inhibitory molecules including PD‐1 and Helios . As a result, a population of PD‐1 + DN T cells is generated.…”

“…As a result, a population of PD‐1 + DN T cells is generated. These cells are functionally impaired but survive for at least 60 days in adoptive transfer recipients . This suggests that self‐reactive former CD8 + cells may be found within the DN T‐cell compartment of normal mice.…”

Pathogenesis of Human Systemic Lupus Erythematosus: A Cellular Perspective

“…For instance, reduced numbers of SLAMF4-expressing memory CD8 + T cells and decreased cytotoxic activity in vitro have been reported in samples from SLE patients [71]. In addition, increased expression of PD-1 in CD8 + T cells from SLE patients, as well as conversion of CD8 + T cells into double-negative T cells, have been related to dampened cytotoxic function in vitro , and to reduced proliferative responses to viral peptides [72]. Indeed, SLAMF4 and its transducer SAP are key molecules involved in cytotoxic responses against Epstein–Barr virus [73].…”