During chronic infection with
Helicobacter pylori
, Schlafen 4-expressing myeloid-derived suppressor cells (SLFN4
+
MDSCs) create a microenvironment favoring intestinal metaplasia and neoplastic transformation. SLFN4 can be induced by IFN-α, which is mainly secreted from plasmacytoid dendritic cells (pDCs). This study tested the hypothesis that
Helicobacter pylori
infection promotes SLFN4
+
MDSC differentiation by inducing pDCs to secrete IFN-α. C57BL/6 mice were gavaged with
H. pylori
and infection lasted 2, 4, or 6 months. The mouse pDCs were isolated from the bone marrow from wild type C57BL/6J mice. The results showed that
H. pylori
infection increased the number of SLFN4
+
MDSCs by inducing IFN-α expression in mice. Further mechanistic experiments unraveled that IFN-α induced SLFN4 transcription by binding to the SLFN4 promoter. Furthermore,
H. pylori
infection stimulated pDCs to secrete IFN-α by activating the TLR9-MyD88-IRF7 pathway. Collectively,
Helicobacter pylori
infection promotes SLFN4
+
MDSC differentiation by inducing secretion of IFN-α from pDCs.