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.
Highlights
The traditional view of the immune system distinguishes innate immunity from adaptive or acquired immunity
Taken together, having availed ourselves of different types of empirical data, we propose that in humans, innate CD8(+) T lymphocytes constitute a new cellular component that could have a role in antitumor immunity
Our results during Chronic Myeloid Leukemia (CML) and ovarian cancer are in favor of the existence of an axis composed of innate T cells with an antitumoral potential, which consist of iNKT cells and innate CD8(+) T lymphocytes
Summary
The traditional view of the immune system distinguishes innate immunity from adaptive or acquired immunity. Björkström et al [33], showed that EMRA(+) KIR(+) CD8(+) T cells have a skewed repertoire using fewer different Vβ than their EMRA(+) KIR(−) CD8(+) T cell counterpart, a finding suggesting the role of antigenic pressure in the acquisition of this phenotype An equivalent to this population of KIR/ NKG2(+) CD8(+) T cells is present in human cord blood, where they possess an EMRA memory phenotype and rapidly express IFN-γ following TCR stimulation [36]. This is a population of T cells that has been educated and has differentiated in the absence of foreign antigenic stimulation, into terminal effector memory T cells.
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