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Background  Tuberculosis (TB) affects one third of the global population, and TB of the central nervous system (CNS-TB) is the most severe form of tuberculosis which often associates with high mortality. The pro-inflammatory cytokine tumour necrosis factor (TNF) plays a critical role in the initial and long-term host immune protection against  Mycobacterium tuberculosis  ( M. tuberculosis ) which involves the activation of innate immune cells and structure maintenance of granulomas. However, the contribution of TNF, in particular neuron-derived TNF, in the control of cerebral  M. tuberculosis  infection and its protective immune responses in the CNS were not clear.    Methods  We generated neuron-specific TNF-deficient (NsTNF −/− ) mice and compared outcomes of disease against TNF f/f  control and global TNF −/−  mice. Mycobacterial burden in brains, lungs and spleens were compared, and cerebral pathology and cellular contributions analysed by microscopy and flow cytometry after  M. tuberculosis  infection. Activation of innate immune cells was measured by flow cytometry and cell function assessed by cytokine and chemokine quantification using enzyme-linked immunosorbent assay (ELISA).    Results  Intracerebral  M. tuberculosis  infection of TNF −/−  mice rendered animals highly susceptible, accompanied by uncontrolled bacilli replication and eventual mortality. In contrast, NsTNF −/−  mice were resistant to infection and presented with a phenotype similar to that in TNF f/f  control mice. Impaired immunity in TNF −/−  mice was associated with altered cytokine and chemokine synthesis in the brain and characterised by a reduced number of activated innate immune cells. Brain pathology reflected enhanced inflammation dominated by neutrophil influx.    Conclusion  Our data show that neuron-derived TNF has a limited role in immune responses, but overall TNF production is necessary for protective immunity against CNS-TB.

TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis