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

Diana M. Elizondo, Temesgen E. Andargie, Naomi L. Haddock, Ricardo L.Louzada da Silva, Tatiana Rodrigues de Moura, Michael W. Lipscomb

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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 languageEnglish (US)
Pages (from-to)123-130
Number of pages8
JournalJournal of Leukocyte Biology
Volume105
Issue number1
DOIs
StatePublished - Jan 2019
Externally publishedYes

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

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