Abstract
Memory formation is a hallmark of T cell-mediated immunity, but how differentiation into either short-lived effector cells (SLECs, CD127−KLRG1+) or memory precursors cells (MPECs, CD127+KLRG1−) and subsequent regulation of long-term memory is adjusted is incompletely understood. Here, we show that loss of the nuclear orphan receptor NR2F6 in germ-line Nr2f6-deficient mice enhances antigen-specific CD8+ memory formation up to 70 days after bacterial infection with Listeria monocytogenes (LmOVA) and boosts inflammatory IFN-γ, TNFα, and IL-2 cytokine recall responses. Adoptive transfer experiments using Nr2f6−/− OT-I T-cells showed that the augmented memory formation is CD8+ T-cell intrinsic. Although the relative difference between the Nr2f6+/+ and Nr2f6−/− OT-I memory compartment declines over time, Nr2f6-deficient OT-I memory T cells mount significantly enhanced IFN-γ responses upon reinfection with increased clonal expansion and improved host antigen-specific CD8+ T-cell responses. Following a secondary adoptive transfer into naïve congenic mice, Nr2f6-deficient OT-I memory T cells are superior in clearing LmOVA infection. Finally, we show that the commitment to enhanced memory within Nr2f6-deficient OT-I T cells is established in the early phases of the antibacterial immune response and is IFN-γ mediated. IFN-γ blocking normalized MPEC formation of Nr2f6-deficient OT-I T cells. Thus, deletion or pharmacological inhibition of NR2F6 in antigen-specific CD8+ T cells may have therapeutic potential for enhancing early IFN-γ production and consequently the functionality of memory CD8+ T cells in vivo.
Highlights
The generation of effector and memory CD8+ T cells is a requirement for the clearance of intracellular pathogens and subsequent long-term protection, and both CD8+ subsets are targets for anticancer immunotherapy and vaccination[1]
Upon restimulation with cognate antigen (N4) on day 7 ex vivo, we observed a significant increase in the fraction of Nr2f6−/− OT-I T cells producing effector cytokines, in particular, triple producing (TP) (IFN-γ+TNF-α+IL-2+) was enhanced (Fig. 2F)
As on d7 adoptive cell transfer (ACT), we did not observe any differences in host CD8+OVAtet+ populations by >d140 after infection (Fig. S5E, F). These results indicate that the phenotypical differences between Nr2f6+/+ and Nr2f6−/− OT-I T cells persist after the contraction phase but disappear long-term (>d140), in both the blood and the spleen
Summary
The generation of effector and memory CD8+ T cells is a requirement for the clearance of intracellular pathogens and subsequent long-term protection, and both CD8+ subsets are targets for anticancer immunotherapy and vaccination[1]. Most effector CD8+ T cells undergo apoptosis, but a small number survives and is maintained as memory CD8+ T-cell pool[2]. Using germ-line knockout mice, we have identified functions of the orphan NR, NR2F6 in effector CD4+ and CD8+ T-lymphocytes during cancer progression, autoimmune responses, and immunization[19,20,21,22,23,24]. Our previous tumor experiments demonstrated that Nr2f6-deficient mice have superior protective memory responses[19]. Set out to further define the intrinsic role of NR2F6 in CD8+ T-cell memory responses
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