Naturally Occurring PD-1+ Memory Phenotype CD8 T Cells Belong to Nonconventional CD8 T Cells and Are Cyclophosphamide-Sensitive Regulatory T Cells

Abstract

CD8 T cells expressing memory markers exist in naive mice and are thought to be of heterogeneous origin. It was recently reported that among such memory-phenotype (MP) CD8 T cells in naive mice, those expressing programmed death-1 (PD-1) had immune regulatory activity, but their origin and relationship with other regulatory CD8 T cell subsets remain unclear. In the current study, we examined detailed characteristics and functions of PD-1+ MP CD8 T cells in naive mice. Their expression pattern of surface molecules resembled that of exhausted CD8 T cells seen in chronic viral infection. However, PD-1+ MP CD8 T cells were detected from neonatal periods, even in the thymus; thus, they are naturally occurring. By analyzing bone marrow chimera mice in which β2-microglobulin–deficient mice were used as the recipients, it was revealed that PD-1+ MP CD8 T cells were positively selected by hematopoietic cells, indicating that they belong to nonconventional CD8 T cells. However, in contrast to majority of MP CD8 T cells, PD-1+ MP CD8 T cells were IL-15 independent. PD-1+ MP CD8 T cells showed the fastest cell cycling among various T cell subsets in naive mice, which was consistent with the highest sensitivity to cyclophosphamide (CP) treatment. Importantly, PD-1+ MP CD8 T cells were able to suppress delayed-type hypersensitivity response that was augmented by CP treatment. Taken together, our data indicate that the naturally occurring PD-1+ MP CD8 T cells in naive mice are a unique subset of nonconventional CD8 T cells and represent the CP-sensitive suppressor CD8 T cells.

LPS stimulates and Hsp70 down-regulates TLR4 to orchestrate differential cytokine response of culture-differentiated innate memory CD8+ T cells

“…Here we show, besides IFN-c the cells under similar conditions produce IL-10. Recently it was reported that a subset of memory-phenotype CD8 + T cells has immunoregulatory activity in naïve mice [13]. IL-10 is critically involved in the action of CD8 + CD122 + Treg cells, a subset of naturally occurring T cells that suppress the proliferation and IFN-c production of CD8 + CD122 À cells.…”

“…However, in contrast to IFN-c, the IL-10 expressing cells and release of IL-10 are higher in BALB/c mice than C57BL/6 mice. Recent studies have shown naturally occurring CD8 + CD122 + cells are also regulatory T (Treg) cells that maintain T cell homeostasis and suppress its responses through secretion of IL-10 [13,31]. Paradoxically, CD8 + CD122 + T cells have been well described as Ag-specific memory T cells [31,32].…”

“…It has been suggested that these Ag-naïve innate memory CD8 + T cells are evolved to rapidly respond during early infection assisting the innate immune response and bridging the Ag-specific adaptive immunity [11,12]. Although these nonconventional CD8 + T cells are implicated for effector functions during innate host defence, identification of a novel subset of naturally occurring nonconventional CD8 T cells have been made which are actually programmed cell death (PD)-1 + CD8 T regulatory cells [13]. Hence, the cells may act as crucial players in long-term immunity versus tolerance.…”

Virtual memory CD8 T cells display unique functional properties

“…S3B) was noteworthy, because this factor is critical in control of several pathogens, including Listeria (44). Furthermore, several studies have suggested that memory-phenotype CD8 T cells from unimmunized mice have regulatory functions (17)(18)(19)(20)(21)(22): Hence, the VM population might inhibit, not elicit pathogen control. To explore this issue, we performed studies to compare VM, naïve, and TM CD8 T cells for protection against virulent LM-OVA infection.…”

“…Such findings raised the possibility that, although displaying memory phenotype, the VM pool retains naïve functional properties or may even be functionally compromised, and hence contribute little to an immune response. Furthermore, several studies suggest that memoryphenotype CD8 T cells (from unimmunized mice) exert a regulatory role, acting to inhibit CD4 and CD8 T-cell responses (17)(18)(19)(20)(21)(22). Whether the antigen-specific VM population serves to restrain, rather than enhance, immune reactivity has not been tested and is especially relevant for their potential role in protective immunity against pathogens.…”