Allograft Inflammatory Factor 1 expression in cDC1 is required to direct Tbet—driven T cell immunity to defend against intracellular pathogens in vivo 2256292

Abstract

Allograft Inflammatory Factor‑1 (AIF1) is a calcium‑binding protein enriched in conventional dendritic cells, with selective expression in cDC1. We hypothesized that AIF1 programs cDC1 immunity to intracellular pathogens by sustaining their activation and T cell‑priming capacity. To directly address, AIF1 was selectively deleted in CD11c+ cells prior to infection with the intracellular or extracellular pathogens in vivo. DC and T cell subsets were then analyzed by multiparametric flow cytometry. Additionally Single-cell RNA sequencing (scRNA-seq) under steady-state conditions was analyzed by differential expression and gene set enrichment (GSEA). Conditional deletion of AIF1 in DCs resulted in a modest (∼20%) reduction of cDC1, without affecting cDC2 populations, indicating a partial lineage dependency. During infection with intracellular pathogens Listeria monocytogenes and LCMV, AIF1‑deficient cDC1 showed impaired activation and defective pathogen control, leading to markedly reduced CD4+ T cell activation, loss of Th1 polarization (CD4+T‑bet+), and diminished CD8+CD54+GranzymeB+ cytotoxic responses. In contrast, infection with extracellular pathogens Helicobacter pylori and Nippostrongylus brasiliensis, eliciting Th2-biased immunity, induced no observable impairment in T cell responses. This aligns with AIF1’s unique expression within cDC1, but not cDC2. These findings identify AIF1 as a critical regulator of cDC1 immunogenic identity and protective T cell immunity to intracellular infection, defining a pathway where AIF1 loss reprograms DC—T cell communication toward a regulatory, non-protective outcome. National Institutes of Health (NIH) Classical and Non-Classical Antigen Presenting Cells (APC)