Phenotype of NK-Like CD8(+) T Cells with Innate Features in Humans and Their Relevance in Cancer Diseases

Abstract

Unconventional T cells are defined by their capacity to respond to signals other than the well-known complex of peptides and major histocompatibility complex proteins. Among the burgeoning family of unconventional T cells, innate-like CD8(+) T cells in the mouse were discovered in the early 2000s. This subset of CD8(+) T cells bears a memory phenotype without having encountered a foreign antigen and can respond to innate-like IL-12 + IL-18 stimulation. Although the concept of innate memory CD8(+) T cells is now well established in mice, whether an equivalent memory NK-like T-cell population exists in humans remains under debate. We recently reported that CD8(+) T cells responding to innate-like IL-12 + IL-18 stimulation and co-expressing the transcription factor Eomesodermin (Eomes) and KIR/NKG2A membrane receptors with a memory/EMRA phenotype may represent a new, functionally distinct innate T cell subset in humans. In this review, after a summary on the known innate CD8(+) T-cell features in the mouse, we propose Eomes together with KIR/NKG2A and CD49d as a signature to standardize the identification of this innate CD8(+) T-cell subset in humans. Next, we discuss IL-4 and IL-15 involvement in the generation of innate CD8(+) T cells and particularly its possible dependency on the promyelocytic leukemia zinc-finger factor expressing iNKT cells, an innate T cell subset well documented for its susceptibility to tumor immune subversion. After that, focusing on cancer diseases, we provide new insights into the potential role of these innate CD8(+) T cells in a physiopathological context in humans. Based on empirical data obtained in cases of chronic myeloid leukemia, a myeloproliferative syndrome controlled by the immune system, and in solid tumors, we observe both the possible contribution of innate CD8(+) T cells to cancer disease control and their susceptibility to tumor immune subversion. Finally, we note that during tumor progression, innate CD8(+) T lymphocytes could be controlled by immune checkpoints. This study significantly contributes to understanding of the role of NK-like CD8(+) T cells and raises the question of the possible involvement of an iNKT/innate CD8(+) T cell axis in cancer.

The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+T cells

“…Taken together, this suggests that these memory-like CD8 + T cells arose independently of foreign antigens, leading us to designate these cells as antigen-independent memory-like T AIM CD8 + cells. Importantly, such unconventional memory-phenotype cells constitute a substantial (15-25%) fraction of the peripheral CD8 + T cell compartment in WT mice and humans 4,35,44,78,79 . The fraction of unconventional memory-phenotype T cells further increases with age 80,81 .…”

Innate T-αβ lymphocytes as new immunological components of anti-tumoral “off-target” effects of the tyrosine kinase inhibitor dasatinib

“…3). We focused our analysis on CD44 + Eomes + CD8 T-cells, hereafter named T MEM cells, that express a high level of CD122 26 and can be considered as all innate-memory T-cells in the thymus. We found that their proportion was highly decreased by dasatinib treatment (Fig.…”

“…Furthermore, concomitantly with NK cell restoration, we showed supra-normalization of innate CD8 T-cell frequency in CML patients in treatment-free remission for over two years 29 . iNKT cells and innate CD8 T-cells being candidates as key players in the immune-surveillance of cancer, we have hypothesized that they are potential targets of dasatinib. Using BALB/c mice because they contain more of these two unconventional subtypes of T-cells 26,30,31 , and peripheral blood material from BCR-ABL + CML patients, we have demonstrated that dasatinib can influence both cell subtypes at functional and/or numerical level(s). experimental studies in animals.…”

“…Recently, another unconventional TCR-αβ cell subset with NK-like properties has aroused our interest: innate CD8 T-cells, originally found in the mouse model (for review, see 26 ). We identified this subset in healthy individuals as a new distinct CD8 T-cell subset characterized by the expression of killer-cell immunoglobulin-like receptors (panKIR/NKG2A) with a memory phenotype (high Eomesodermin (Eomes) expression) and prompt IFNγ production in response to the pro-inflammatory cytokines IL-12 and IL-18 27 .…”

“…We identified this subset in healthy individuals as a new distinct CD8 T-cell subset characterized by the expression of killer-cell immunoglobulin-like receptors (panKIR/NKG2A) with a memory phenotype (high Eomesodermin (Eomes) expression) and prompt IFNγ production in response to the pro-inflammatory cytokines IL-12 and IL-18 27 . Like iNKT cells, innate CD8 T-cells are present in several tumors 26 , especially in CML with a reduced number and function at diagnosis but partial normalization in patients in remission under TKI therapy 28 . Furthermore, concomitantly with NK cell restoration, we showed supra-normalization of innate CD8 T-cell frequency in CML patients in treatment-free remission for over two years 29 . iNKT cells and innate CD8 T-cells being candidates as key players in the immune-surveillance of cancer, we have hypothesized that they are potential targets of dasatinib.…”