T cell-derived tumour necrosis factor is essential, but not sufficient, for protection againstMycobacterium tuberculosisinfection

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Abstract
SUMMARY: Tumour necrosis factor (TNF) is critical for sustained protective immunity against Mycobacterium tuberculosis infection. To investigate the relative contributions of macrophage- and T cell-derived TNF towards this immunity T cells from wild-type (WT) or TNF–/– mice were transferred into RAG–/– or TNF–/– mice which were then infected with M. tuberculosis. Infected RAG–/– mice and RAG–/– recipients of TNF deficient T cells developed overwhelming infection, with extensive pulmonary and hepatic necrosis and succumbed with a median of only 16 days infection. By contrast, RAG–/– recipients of WT T cells showed a significant increase in survival with a median of 32 days. Although initial bacterial growth was similar in all groups of RAG–/– mice, the transfer of WT, but not TNF–/–, T cells led to the formation of discrete foci of leucocytes and macrophages and delayed the development of necrotizing pathology. To determine requirements for macrophage-derived TNF, WT or TNF–/– T cells were transferred into TNF–/– mice at the time of M. tuberculosis infection. Transfer of WT T cells significantly prolonged survival and reduced the early tissue necrosis evident in the TNF–/– mice, however, these mice eventually succumbed indicating that T cell-derived TNF alone is insufficient to control the infection. Therefore, both T cell- and macrophage-derived TNF play distinct roles in orchestrating the protective inflammatory response and enhancing survival during M. tuberculosis infection.

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