We demonstrate that disturbed macrophage–IEC interactions, caused by PTPN2 deletion in either macrophages or IECs, has detrimental consequences for the host’s ability to defeat enteric pathogens and that PTPN2 loss promotes susceptibility to infection with C. rodentium, a model organism of enterohemorrhagic E. coli infections in humans. The gene discussed is PTPN2; the disease is infection.