Abstract
Tuberculosis of the central nervous system (CNS-TB) is a devastating complication of tuberculosis, and tumor necrosis factor (TNF) is crucial for innate immunity and controlling the infection. TNF is produced by many cell types upon activation, in particularly the myeloid and T cells during neuroinflammation. Here we used mice with TNF ablation targeted to myeloid and T cell (MT-TNF−/−) to assess the contribution of myeloid and T cell-derived TNF in immune responses during CNS-TB. These mice exhibited impaired innate immunity and high susceptibility to cerebral Mycobacterium tuberculosis infection, a similar phenotype to complete TNF-deficient mice. Further, MT-TNF−/− mice were not able to control T cell responses and cytokine/chemokine production. Thus, our data suggested that collective TNF production by both myeloid and T cells are required to provide overall protective immunity against CNS-TB infection.
Highlights
Tumor necrosis factor (TNF) is a pleiotropic cytokine involved in protective cell-mediated immunity against mycobacterial infection
To address the contribution of TNF derived from myeloid and T cells in protective immunity against CNS-TB, we intracerebrally challenged the mice with M. tuberculosis and compared disease progression in various cell-specific TNF-deficient mice, including myeloid specific (MN-TNF−/−), T-cell specific (T-TNF−/−), and TNF deficient in both myeloid and T-cells (MT-TNF−/−)
We found that MN-TNF−/− and T-TNF−/− mice survived the infection similar to wild-type TNFf/f mice (Table 1); TNF deficiency in either myeloid cells or T cells had no effects on the overall protection against cerebral tuberculosis
Summary
Tumor necrosis factor (TNF) is a pleiotropic cytokine involved in protective cell-mediated immunity against mycobacterial infection. Mutation of the leukotriene A4 hydrolase locus, which controls the balance of pro- and anti-inflammatory eicosanoids, showed two distinct molecular routes to mycobacterial susceptibility converging on dysregulated levels of TNF [5, 6]. Earlier animal models of CNS-TB enabled investigation of therapeutic strategies and understanding of immune regulation during CNS-TB despite the limitation in the route of pathogen entry to the CNS [9,10,11]. Similar cytokine profile was observed as in CNS-TB patients [12, 13], and the genetic deficiencies of immune effectors such as TNF and iNOS have confirmed its importance as critical for immune protection against tuberculosis in the CNS [14, 15]
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