Abstract
Allograft inflammatory factor-1 (AIF1) is a cytoplasmic scaffold protein shown to influence immune responses in macrophages and microglial cells. The protein contains Ca2+ binding EF-hand and PDZ interaction domains important for mediating intracellular signaling complexes. This study now reports that AIF1 is expressed in CD11c+ dendritic cells (DC) and silencing of expression restrains induction of antigen-specific CD4+ T cell effector responses. AIF1 knockdown in murine DC resulted in impaired T cell proliferation and skewed polarization away from T helper type 1 and 17 fates. In turn, there was a parallel expansion of IL-10-producing and CD25+Foxp3+ T regulatory subsets. These studies are the first to demonstrate that AIF1 expression in DC serves as a potent governor of cognate T cell responses and presents a novel target for engineering tolerogenic DC-based immunotherapies.
Highlights
Dendritic cells (DC) are professional antigen presenting cells that direct T cell activation, proliferation, and polarization [1, 2]
This study reports that Allograft inflammatory factor-1 (AIF1) is expressed in CD11c+ dendritic cells (DC) and silencing of expression restrains induction of antigen-specific CD4+ T cell effector responses
LPS and IFNγ stimulation resulted in significant increase in AIF1 expression in these MHC class II+CD11c+ subsets
Summary
Dendritic cells (DC) are professional antigen presenting cells that direct T cell activation, proliferation, and polarization [1, 2]. In addition to directing immunity, DC play prominent roles in modulating peripheral tolerance by inducing anergic states in responder T cells and/or directing fates toward T regulatory cell (Treg) states [3,4,5]. The biological factors and mechanisms that govern direction toward immunity vs tolerance by DC are not fully understood. Allograft inflammatory factor-1 (AIF1), known as ionized calcium-binding adapter molecule 1, is a 17 kD interferon gamma-inducible calcium-binding EF-hand protein [6, 7]. The gene, situated in the major histocompatibility class III genomic region [8], has demonstrated diverse roles in both the nervous and immune systems [9,10,11,12,13]. It is largely restricted to the monocyte and macrophage lineages. Expression of AIF1 in macrophages has been shown
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