Prominent role for T cell-derived Tumour Necrosis Factor for sustained control of Mycobacterium tuberculosis infection

Abstract

Tumour Necrosis Factor (TNF) is critical for host control of M. tuberculosis, but the relative contribution of TNF from innate and adaptive immune responses during tuberculosis infection is unclear. Myeloid versus T-cell-derived TNF function in tuberculosis was investigated using cell type-specific TNF deletion. Mice deficient for TNF expression in macrophages/neutrophils displayed early, transient susceptibility to M. tuberculosis but recruited activated, TNF-producing CD4+ and CD8+ T-cells and controlled chronic infection. Strikingly, deficient TNF expression in T-cells resulted in early control but susceptibility and eventual mortality during chronic infection with increased pulmonary pathology. TNF inactivation in both myeloid and T-cells rendered mice critically susceptible to infection with a phenotype resembling complete TNF deficient mice, indicating that myeloid and T-cells are the primary TNF sources collaborating for host control of tuberculosis. Thus, while TNF from myeloid cells mediates early immune function, T-cell derived TNF is essential to sustain protection during chronic tuberculosis infection.

Cell-type–restricted anti-cytokine therapy: TNF inhibition from one pathogenic source

“…Taking this into account, a possible improvement of existing anti-TNF therapeutic options by selective inhibition of TNF produced by macrophages appears reasonable. A recent study demonstrated that for the resistance to Mycobacterium tuberculosis infection in mice T-cell-derived TNF appears critical and nonredundant for immune protection (41). This is consistent with the mode of protection through the formation of bactericidal granulomas whose structural integrity depends on TNF produced by T cells, presumably in membrane-bound form (41,42).…”

“…A recent study demonstrated that for the resistance to Mycobacterium tuberculosis infection in mice T-cell-derived TNF appears critical and nonredundant for immune protection (41). This is consistent with the mode of protection through the formation of bactericidal granulomas whose structural integrity depends on TNF produced by T cells, presumably in membrane-bound form (41,42). In both humans and mice, systemic anti-TNF treatment is known to affect granuloma integrity and may cause reactivation of latent disease (43).…”

Adaptive immunity to murine skin commensals

“…We did not evaluate TNF, which would be another candidate because TNF −/− mice and humans treated with TNF antagonists are susceptible to mycobacterial infection. It has been shown that both Tcell and myeloid-cell TNF are required for mycobacterial control in mice (54). IL-22 deficiency did not impair the effect of transferred T cells in reducing bacterial transcripts in Rag −/− lymph nodes.…”

Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: Immunity interruptus

“…Finally, TNF has a variety of immunoregulatory actions including promoting granuloma integrity. Elucidating how TNF contributes to anti-mycobacterial defense is complicated because multiple cell types produce it [141]. Allie et al investigated cell type specific TNF −/− mice and found that while myeloid cell expression of TNF is important for cell recruitment to the lung, initiation of T cell immunity and establishment of lung lesions appeared normal [141].…”

“…Elucidating how TNF contributes to anti-mycobacterial defense is complicated because multiple cell types produce it [141]. Allie et al investigated cell type specific TNF −/− mice and found that while myeloid cell expression of TNF is important for cell recruitment to the lung, initiation of T cell immunity and establishment of lung lesions appeared normal [141]. In contrast, mice with a T cell-specific TNF −/− were unable to control the infection during the chronic phase of the infection and died prematurely.…”