Allograft Inflammatory Factor-1 regulates immune activation states and is required for effective pathogen-specific T cell immunity during infection

Allograft inflammatory factor-1 (AIF1) is a scaffold protein expressed predominantly in myeloid antigen-presenting cells (APCs) and associated with inflammatory disease. Although genetic studies have linked AIF1 loci to immune traits, its causal role in physiological immune responses remains poorly defined. We examined AIF1 deficiency using a conditional knockout model with deletion of AIF1 in hematopoietic cells (AIF1-cKO) during development and challenged mice with Listeria monocytogenes. AIF1 loss impaired bacterial clearance and diminished inflammatory responses, indicating reduced immune readiness during infection. AIF1-cKO mice exhibited impaired expansion of antigen-specific CD4+ and CD8+ T cells, accompanied by regulatory-associated phenotypic changes. These defects were associated with reduced cDC1 frequencies and transcriptional and phenotypic remodeling of splenic macrophages toward a less inflammatory state. Single-cell RNA sequencing revealed transcriptional alterations across multiple myeloid and lymphoid compartments despite AIF1 expression being largely restricted to myeloid APC, indicating broader immune remodeling. Increased Tgfbr1 expression was a recurrent feature across several immune populations. Consistent with this finding, AIF1-deficient cells displayed enhanced TGF{beta} responsiveness, while Tgfbr1 silencing partially restored inflammatory responses and T cell priming ex vivo. These findings establish AIF1 as a regulator of immune competence that promotes effective innate and adaptive immune responses.