Abstract
<jats:p>Allograft inflammatory factor-1 (AIF1) is a scaffold protein enriched in myeloid antigen-presenting cells (APC) and linked to inflammatory disease. Although genetic studies associate AIF1 loci with immune traits, its causal role in physiological immune responses remains poorly defined. We examined AIF1 deficiency using a hematopoietic-restricted conditional knockout (cKO) model challenged with Listeria monocytogenes. AIF1 loss impaired bacterial clearance and blunted host inflammatory responses, indicating reduced immune readiness during intracellular infection. AIF1-cKO mice exhibited defective expansion of antigen-specific CD4+ and CD8+ T cells, accompanied by skewing toward regulatory-like phenotypes. These defects were associated with reduced cDC1 frequencies and transcriptional and phenotypic remodeling of splenic macrophages toward a less inflammatory state. scRNA-seq 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. Consistently, AIF1-deficient cells displayed enhanced TGFβ responsiveness, with Tgfbr1 silencing partially restored inflammatory responses and T cell priming ex vivo. These findings establish AIF1 as a regulator of immune competence that supports immune readiness for driving effective innate and adaptive responses to pathogen infections.</jats:p>