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Background  Several activities of the transmembrane form of TNF (memTNF) in immune responses to intracellular bacterial infection have been shown to be different from those exerted by soluble TNF. Evidence is based largely on studies in transgenic mice expressing memTNF, but precise cellular mechanisms are not well defined and the importance of TNF receptor regulation is unknown. In addition, memTNF activities are defined for a particular modification of the extracellular domain of TNF but a direct comparison of different mutant memTNF molecules has not been done  in vivo .    Methodology  To understand the activities of memTNF we compared two commonly used mouse strains lacking soluble TNF but possessing functional and normally regulated membrane-bound TNF knockin (memTNF KI) for their capacity to generate cell-mediated immune responses and resistance to  M. bovis  BCG infection, and to regulate TNF receptors.    Principal Findings    M. bovis  BCG infection resulted in similar bacterial loads in one strain of memTNF KI (memTNF Δ1–9,K11E ) and in wild-type mice, in contrast, the other strain of memTNF KI mice (memTNF Δ1–12 ) showed higher sensitivity to infection with high mortality (75%), greater bacterial load and massive lung pathology. The pattern of cytokines/chemokines, inflammatory cells, pulmonary NF-κB phosphorylation, antigen-dependent IFN-γ response, and splenic iNOS was impaired in  M. bovis  BCG-infected memTNF Δ1–12  KI mice. Macrophages expressing TNFR2 were reduced but soluble TNFRs were higher in memTNF Δ1–12  KI mice during the infection.  In vitro ,  M. bovis  BCG-induced NF-κB activation and cytokines were also decreased in memTNF Δ1–12  KI bone marrow-derived macrophages.    Conclusion  Our data show that two memTNF molecules exerted very different activities upon  M. bovis  BCG infection resulting in protection or not to bacterial infection. These results suggest a regulatory mechanism of memTNF and TNF receptors being critical in the outcome of the infection and highlight the role of cell-bound and soluble TNFR2 in memTNF-mediated anti-microbial mechanisms.

plos one

Membrane-Bound TNF Induces Protective Immune Responses to M. bovis BCG Infection: Regulation of memTNF and TNF Receptors Comparing Two memTNF Molecules