EOMESODERMIN-EXPRESSING INNATE-LIKE CD8+ T CELLS IN HUMANS ARE IMPAIRED IN CHRONIC MYELOID LEUKEMIA PATIENTS AT DIAGNOSIS

Abstract

Abstract Starting with our recent identification in healthy individuals of a new distinct CD8+ T cell subset harboring Eomes and exhibiting a marked “innate” (panKIR/NKG2A+) phenotype, we present here the first report on this unique T cell population in a physiopathological context, namely chronic myelogenous leukemia (CML), a clonal myeloproliferative disorder. The current first-line therapies for this hematopoietic malignancy are tyrosine kinase inhibitors such as Imatinib (IM). Knowing that the generation of innate Eomes-expressing CD8+ T cells in mice depends on PLZF-expressing NKT cells and that iNKT cells are functionally deficient in CML, we surmised that panKIR/NKG2A+Eomes+ CD8+ T cells could be altered during CML. Accordingly, in CML patients at diagnosis, the pool of blood KIR/NKG2A(+)Eomes(+) CD8(+) T cells was found to be severely reduced. Moreover, like for iNKT and NK cells, the functions of these innate-like CD8(+) T cells were impaired, as attested by their lost of potent antigen-independent cytotoxic activity and IFN-γ production in response to innate-like stimulation by IL-12+IL-18. Remarkably, both innate-like CD8(+) T cells and iNKT cells returned to normal after complete CML remission upon IM therapy, supporting evidence for an iNKT cell-dependent generation of circulating KIR/NKG2A+Eomes+ CD8+ T cells in CML patients, as in mice. Our study reveals a possible contribution of iNKT/innate-like CD8(+) T cells as a new innate immune axis to tumor control in CML.