FLT3L-induced virtual memory CD8 T cells engage the immune system against tumors.

BACKGROUND: Previous research in FMS-like tyrosine kinase 3 ligands (FLT3L) has primarily focused on their potential to generate dendritic cells (DCs) from bone marrow progenitors, with a limited understanding of how these cells affect CD8 T cell function. In this study, we further investigated the in vivo role of FLT3L for the immunomodulatory capabilities of CD8 T cells. METHODS: Albumin-conjugated FLT3L (Alb-FLT3L) was generated and applied for translational medicine purposes; here it was used to treat naïve C57BL/6 and OT1 mice for CD8 T cell response analysis. Syngeneic B16ova and E.G7ova mouse models were employed for adoptive cell transfer to evaluate the effects of Alb-FLT3L preconditioning of CD8 T cells on tumor progression. To uncover the underlying mechanisms of Alb-FLT3L modulation, we conducted bulk RNA-seq analysis of the CD44high CD8 T cells. STAT1-deficient mice were used to elucidate the functional roles of Alb-FLT3L in the modulation of T cells. Finally, antibody blockade of type one interferon signaling and in vitro coculture of plasmacytoid DCs (pDCs) with naive CD8 T cells was performed to determine the role of pDCs in mediating regulation of CD44high CD8 T cells. RESULTS: CD44high CD8 T cells were enhanced in C57BL/6 mice administrated with Alb-FLT3L. These CD8 T cells exhibited virtual memory features and had greater proliferative and effective functions. Notably, the adoptive transfer of CD44high naïve CD8 T cells into C57BL/6 mice with B16ova tumors led to significant tumor regression. RNA-seq analysis of the CD44high naïve CD8 T cells revealed FLT3L to induce CD44high CD8 T cells in a JAK-STAT1 signaling pathway-dependent manner, as supported by results indicating a decreased ability of FLT3L to enhance CD8 T cell proliferation in STAT1-deficient mice as compared to wild-type control mice. Moreover, antibody blockade of type one interferon signaling restricted the generation of FLT3L-induced CD44high CD8 T cells, while CD44 expression was able to be induced in naïve CD8 T cells cocultured with pDCs derived from FLT3L-treated mice. This suggests the crucial role of pDCs in mediating FLT3L regulation of CD44high CD8 T cells. CONCLUSIONS: These findings provide critical insight and support the therapeutic potential of Alb-FLT3L as an immune modulator in preconditioning of naïve CD8 T cells for cancer immunotherapy.

Strategic ambiguities in the process of consent: role of the family in decisions to forgo life-sustaining treatment for incompetent elderly patients.

This paper evaluates the Hong Kong approach to consent regarding the forgoing of life-sustaining treatment for incompetent elderly patients. It analyzes the contextualized approach in the Hong Kong process-based, consensus-building model, in contrast to other role-based models which emphasize the establishment of a system of formal laws and a clear locus of decisional authority. Without embracing relativism, the paper argues that the Hong Kong model offers an instructive example of how strategic ambiguities can both make good sense within particular cultural context and serve important moral goals.

Perception of environmental hazards in Hong Kong Chinese.

A public sample of Hong Kong Chinese (N = 167) rated the levels of threat of 25 environmental hazards and gave quantitative judgments to six risk characteristics for each hazard. It was found that women, older participants, and less educated individuals found the hazards to be more threatening to the environment than did men, younger participants, and more educated individuals, respectively. A new spatial model emerged from a principal component analysis carried out on responses to six risk characteristics. Instead of replicating the well-documented factors of unknown risk versus dread risk, we found a structure defined by a known and dread risk factor and a controllable risk factor. Findings were discussed in light of potential influences of the Confucian heritage on the perception of risks among Hong Kong Chinese.