Interferon regulatory factor 8-deficiency determines massive neutrophil recruitment but T cell defect in fast growing granulomas during tuberculosis.

Following Mycobacterium tuberculosis (Mtb) infection, immune cell recruitment in lungs is pivotal in establishing protective
immunity through granuloma formation and neogenesis of lymphoid structures (LS). Interferon regulatory factor-8 (IRF-8)
plays an important role in host defense against Mtb, although the mechanisms driving anti-mycobacterial immunity remain
unclear. In this study, IRF-8 deficient mice (IRF-82/2) were aerogenously infected with a low-dose Mtb Erdman virulent strain
and the course of infection was compared with that induced in wild-type (WT-B6) counterparts. Tuberculosis (TB)
progression was examined in both groups using pathological, microbiological and immunological parameters. Following
Mtb exposure, the bacterial load in lungs and spleens progressed comparably in the two groups for two weeks, after which
IRF-82/2 mice developed a fatal acute TB whereas in WT-B6 the disease reached a chronic stage. In lungs of IRF-82/2,
uncontrolled growth of pulmonary granulomas and impaired development of LS were observed, associated with
unbalanced homeostatic chemokines, progressive loss of infiltrating T lymphocytes and massive prevalence of neutrophils
at late infection stages. Our data define IRF-8 as an essential factor for the maintenance of proper immune cell recruitment
in granulomas and LS required to restrain Mtb infection. Moreover, IRF-82/2 mice, relying on a common human and mouse
genetic mutation linked to susceptibility/severity of mycobacterial diseases, represent a valuable model of acute TB for
comparative studies with chronically-infected congenic WT-B6 for dissecting protective and pathological immune reactions.