The Hypothesis of the Human iNKT/Innate CD8(+) T-Cell Axis Applied to Cancer: Evidence for a Deficiency in Chronic Myeloid Leukemia

Abstract

We recently identified a new human subset of NK-like [KIR/NKG2A(+)] CD8(+) T cells with a marked/memory phenotype, high Eomesodermin expression, potent antigen-independent cytotoxic activity, and the capacity to generate IFN-γ rapidly after exposure to pro-inflammatory cytokines. These features support the hypothesis that this new member of the innate T cell family in humans, hereafter referred to as innate CD8(+) T cells, has a role in cancer immune surveillance analogous to invariant natural killer T (iNKT) cells. Here, we report the first quantitative and functional analysis of innate CD8(+) T cells in a physiopathological context in humans, namely chronic myeloid leukemia (CML), a well-characterized myeloproliferative disorder. We have chosen CML based on our previous report that IL-4 production by iNKT cells was deficient in CML patients at diagnosis and considering the recent evidence in mice that IL-4 promotes the generation/differentiation of innate CD8(+) T cells. We found that the pool of innate CD8(+) T cells was severely reduced in the blood of CML patients at diagnosis. Moreover, like iNKT and NK cells, innate CD8(+) T cells were functionally impaired, as attested by their loss of antigen-independent cytotoxic activity and IFN-γ production in response to innate-like stimulation with IL-12 + IL-18. Remarkably, as previously reported for IL-4 production by iNKT cells, both quantitative and functional deficiencies of innate CD8(+) T cells were at least partially corrected in patients having achieved complete cytogenetic remission following tyrosine kinase inhibitor therapy. Finally, direct correlation between the functional potential of innate CD8(+) T and iNKT cells was found when considering all healthy donors and CML patients in diagnosis and remission, in accordance with the iNKT cell-dependent generation of innate CD8(+) T cells reported in mice. All in all, our data demonstrate that CML is associated with deficiencies of innate CD8(+) T cells that are restored upon remission, thereby suggesting their possible contribution to disease control. More generally, our study strongly supports the existence of an innate iNKT/innate CD8(+) T-cell axis in humans and reveals its potential contribution to the restoration of tumor immune surveillance.

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

“…These features validate the KIR/NKG2A(+) Eomes(+) CD8(+) T-cell compartment as a new member of the innate T cell family in humans, and we have termed them innate CD8(+) T cells (41). …”

“…Interestingly, our own results (38) have shown a relation of proportionality between PLZF expression in T and iNKT lymphocytes and Eomes expression by innate CD8(+) T cells in cord blood, suggesting that iNKT cells control the differentiation of human innate CD8(+) T cells. Our results in vitro (41) suggest that IL-4 favors Eomes expression and the generation and/or expansion of human innate CD8(+) T cells.…”

“…In analysis of a cohort of CP patients and those in complete remission, we have observed a correlation between Eomes expression by innate CD8(+) T cells and PLZF expression by iNKT cells (41). This finding underscores the possible pathophysiological significance of IL-4 expression by iNKT cells in CML patients; while deficient during the CP, IL-4 expression is restored in remission (63) and could determine the status of innate CD8(+) T cells during the disease or its treatment.…”

“…There exists a major defect in the innate CD8(+) T cells of chronic phase of CML (CML-CP) patients compared to those of healthy subjects or patients in complete remission following TKI treatment (41). This numerical defect is associated with a loss of IFN-γ expression after innate-like stimulation by IL-12 + IL-18 cytokines and with a loss of degranulation after stimulation via CD16.…”

Tonic Signals: Why Do Lymphocytes Bother?

“…However, it has been unclear from studies of mice with BCR signaling mutations whether antigen is required or whether purely tonic BCR signals are sufficient for splenic follicular B cell development [12,14,40,41]. Certainly, antigen-driven selection into the innate-like B-1a compartment is well-appreciated, while strong BCR signaling disfavors adoption of marginal zone B cell fate [13,42–44]. Prior work has supplied indirect evidence for antigen-dependent positive selection of follicular B cells [12,14,40]; studies have shown that self-ligands can drive selection of B cells into the mature primary immune repertoire [45] and analysis of antigen receptor repertoire diversity has revealed a restricted repertoire in mature relative to immature B cells [46–48].…”