Transmembrane TNF is sufficient to initiate cell migration and granuloma formation and provide acute, but not long-term, control of Mycobacterium tuberculosis infection.
TNF is critical for immunity against Mycobacterium tuberculosis infection; however, the relative contributions of the soluble and transmembrane forms of TNF in this immunity are unknown. Using memTNF mice, which express only the transmembrane form of TNF, we have addressed this question. Wild-type (WT), TNF-/-, and transmembrane TNF (memTNF) mice were infected with M. tuberculosis by aerosol. TNF-/- mice developed overwhelming infection with extensive pulmonary necrosis and died after only 33 days. memTNF mice, like WT mice, contained bacterial growth for over 16 wk, developed an Ag-specific T cell response, and initially displayed compact granulomas, comprised of both lymphocytes and macrophages. Expression of mRNA for the chemokines CXCL10, CCL3, CCL5, and CCL7 was comparable in both WT and memTNF mice. As the infection progressed, however, the pulmonary lesions in memTNF mice became larger and more diffuse, with increased neutrophil accumulation and necrosis. This was accompanied by increased influx of activated memory T cells into the lungs of memTNF mice. Eventually, these mice succumbed to infection with a mean time to death of 170 days. The expression of memTNF on T cells is functionally important because the transfer of T cells from memTNF, but not TNF-/- mice, into either RAG-/- or TNF-/- mice conferred the same survival advantage on the M. tuberculosis-infected recipient mice, as the transfer of WT T cells. Therefore, memTNF, in the absence of soluble TNF, is sufficient to control acute, but not chronic, M. tuberculosis infection, in part through its expression on T cells.
Saunders
Bernadette M
BM
Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales, Australia. b.saunders@centenary.usyd.edu.au
Tran
Stephen
S
Ruuls
Sigrid
S
Sedgwick
Jonathon D
JD
Briscoe
Helen
H
Britton
Warwick J
WJ
D000818:Animals; D001483:Base Sequence; D002465:Cell Movement; D018925:Chemokines / Q000235:genetics; D004247:DNA / Q000235:genetics; D005260:Female; D006099:Granuloma / Q000209:etiology / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000276:immunology / Q000472:pathogenicity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D018925:Chemokines; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C064658:RAG-1 protein; D004247:DNA