Abstract
Allograft Inflammatory Factor-1 (AIF1) is a cytoplasmic scaffold protein that contains Ca 2+ 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.
Original language | English (US) |
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Pages (from-to) | 123-130 |
Number of pages | 8 |
Journal | Journal of Leukocyte Biology |
Volume | 105 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2019 |
Externally published | Yes |
Bibliographical note
Funding Information:This work was funded, in part, by the U.S. National Institutes of Health (Grant #SC1GM127207 and #SC2GM103741), Department of Defense (Grant #W911NF-14-1-0123), and National Science Foundation (Grant #1428768). The authors are grateful to Franklin Ampy, Clarence M. Lee, and Winston Anderson for assistance with statistical analyses and revision of the work.
Publisher Copyright:
©2018 Society for Leukocyte Biology
Keywords
- Tregs
- cytotoxic T cells
- dendritic cells
- programmed death-1
- suppression
- tolerogenic