IL‐10 producing CD8+ CD122+ PD‐1+ regulatory T cells are expanded by dendritic cells silenced for Allograft Inflammatory Factor‐1

[摘要] Allograft Inflammatory Factor‐1 (AIF1) is a cytoplasmic scaffold protein that contains Ca²⁺ binding EF‐hand and PDZ interaction domains important for mediating intracellular signaling complexes in immune cells. The protein plays a dominant role in both macrophage‐ and dendritic cell (DC)‐mediated inflammatory responses. This study now reports that AIF1 expression in DC is important in directing CD8⁺ T cell effector responses. Silencing AIF1 expression in murine CD11c⁺ DC suppressed antigen‐specific CD8⁺ T cell activation, marked by reduced CXCR3, IFNγ and Granzyme B expression, and restrained proliferation. These primed CD8⁺ T cells had impaired cytotoxic killing of target cells in vitro. In turn, studies identified that AIF1 silencing in DC robustly expanded IL‐10 producing CD8⁺ CD122⁺ PD‐1⁺ regulatory T cells that suppressed neighboring immune effector responses through both IL‐10 and PD‐1‐dependent mechanisms. In vivo studies recapitulated bystander suppression of antigen‐responsive CD4⁺ T cells by the CD8⁺ Tregs expanded from the AIF1 silenced DC. These studies further demonstrate that AIF1 expression in DC serves as a potent governor of cognate T cell responses and present a novel target for engineering tolerogenic DC‐based immunotherapies.

[学科分类] 生理学

[关键词] cytotoxic T cells;dendritic cells;programmed death‐1;suppression;tolerogenic;Tregs