Inherited human TNF deficiency undermines macrophages respiratory burst and underlies recurrent pulmonary tuberculosis

Severe inherited defects of human IFN-gamma immunity confer a predisposition to both BCG disease and tuberculosis, whereas milder defects confer a predisposition only to tuberculosis. We report two adults with recurrent pulmonary tuberculosis homozygous for the same private loss-of-function TNF variant. Neither displays other clinical phenotypes, including BCG disease; both patients mount normal clinical and biological inflammatory responses. Their leukocytes, including blood monocytes and monocyte-derived macrophages (MDMs), do not produce TNF. The development of their blood myeloid and lymphoid leukocyte subsets is normal, as is their TNFR1 and TNFR2 expression. However, an impairment of the respiratory burst was observed in vitro in GM-CSF-matured MDMs and alveolar macrophage-like cells (AMLs) from the TNF-deficient patients, TNF- or TNFR1-deficient gene-edited iPSC-derived GM-CSF-matured macrophages, in healthy control MDMs and AMLs differentiated with TNF blockers, as well as ex vivo in lung macrophages treated with TNF blockers. These findings contrast with those for patients with an inherited deficit of the respiratory burst across all types of phagocytes, including neutrophils and monocytes, who are prone to both BCG disease and tuberculosis. The priming of TNF-deficient iPSC-derived macrophages with TNF rescued the respiratory burst. TNF deficiency did not impair IFN-gamma production by lymphocytes or the response to IFN-gamma in macrophages. Human TNF is, thus, required for respiratory burst-dependent IFN-gamma-independent immunity to Mycobacterium tuberculosis in macrophages, but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and other infectious agents.