Chemotherapy-Resistant T Cells

Abstract SCI-51

The mechanisms that maintain human T cell memory during normal and perturbed homeostasis are not fully understood. Patients undergoing multiple cycles of cytotoxic chemotherapy infrequently develop infections with viruses that are controlled by memory CD8⁺ T cells either during or after the period of profound lymphocytopenia, suggesting that some memory cells survive chemotherapy and provide protective immunity. We recently identified a subset of quiescent human CD161^hi CD8⁺ T cells characterized by the capacity to rapidly efflux cytotoxic drugs and the fluorescent dye, rhodamine 123 (Rh123), which endowed them with the ability to survive chemotherapy in vitro and in vivo and to contribute to the recovery of lymphocyte numbers in patients receiving chemotherapy. Rh123 effluxing CD161^hi memory CD8⁺ cells were identified in both the CD62L⁺ central memory (CM) and CD62L^- effector memory (EM) pools, and were characterized by uniform expression of CD28, high levels of bcl-2, and low levels of granzyme B and perforin. CD161 and CD62L expression allowed partitioning of the CD8⁺ memory compartment into four phenotypic subsets with distinct transcriptional profiles and functional properties. Gene expression profiling of Rh123 effluxing CD161^hi memory CD8⁺ cells in both CM and EM pools revealed a type 17 differentiation program with high levels of RORC, RORA, IL23R, CCR6, KLRB1, and CCL20, compared with CD161^lo CM and EM cells. Transcriptional profiling also revealed alterations in the T cell receptor (TCR) signaling pathway in CD161^hi cells that limits their capacity to proliferate and secrete cytokines, including IL-17, after TCR stimulation. Despite stringent regulation of TCR signaling in type 17-programmed CD161^hi cells, proliferation and cytokine secretion could be induced by ligating CD28 to provide costimulation, and by IL-1β, IL-12, IL-18 or IL-23. The nature of the second and third signals provided to CD161^hi T cells revealed plasticity in this subset of cells and determined whether the CD161^hi progeny derived after expansion had the capacity to secrete IL-17, or had differentiated to Tc1-like cells with restored capacity to proliferate to TCR ligation alone. Thus, a surprisingly large fraction of the human CD8⁺ T cell memory pool is comprised of CD161^hi CD8⁺ T cells that express a type 17 transcriptional program and possess drug efflux capacity that allows them to survive cytotoxic chemotherapy and contribute to recovery of lymphocyte numbers. The stringent regulation of CD8⁺CD161⁺ memory T cells in normal physiology also suggests that this subset may have a potential role in the pathogenesis of IL-17-mediated inflammatory diseases.