Afferent phase production of TNF-alpha is required for the development of protective T cell immunity to Cryptococcus neoformans.
The development of T cell immunity is required to clear a pulmonary Cryptococcus neoformans infection (via the recruitment and activation of inflammatory cells). The objective of our studies was to determine whether TNF-alpha is required during the afferent phase of the response. The levels of TNF-alpha mRNA and protein in the lungs increased following intratracheal inoculation of CBA/J mice with C. neoformans 52 and preceded the development of an inflammatory response in the lungs. Administration of neutralizing TNF-alpha-specific antiserum on days 0, 3, 6, and 9 reduced inflammatory cell recruitment by 80% on day 13, resulting in a 3-fold increase in lung C. neoformans CFU. The number of CD4+ T cells was decreased by 65%, the number of neutrophils was decreased by 84%, and the number of macrophages was decreased by >98%. Strikingly, a single dose of neutralizing anti-TNF-alpha serum was sufficient to prevent the development of protective cell-mediated immunity on day 35 if administered on day 0, but was ineffective if delayed until day 14. Day 0 anti-TNF-alpha-treated mice could not generate cryptococcus-specific delayed type hypersensitivity reactivity, clear the infection from their lungs (10(4)-fold increase in CFU), control dissemination to the spleen and brain (10(5)- and 10(6)-fold increases in CFU), or adoptively transfer cryptococcus-specific immunity (mononuclear cell recruitment into the lungs following intratracheal challenge or footpad delayed type hypersensitivity). Thus, the production of TNF-alpha during the afferent phase of the immune response against a pulmonary C. neoformans infection (before day 14) is critical for the development of protective T cell immunity in both the lungs and extrapulmonary sites.
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109, USA.
G B
GB
Huffnagle
G B
GB
Toews
M D
MD
Burdick
M B
MB
Boyd
K S
KS
McAllister
R A
RA
McDonald
S L
SL
Kunkel
R M
RM
Strieter
D000818:Animals; D003453:Cryptococcosis / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D003455:Cryptococcus neoformans / Q000276:immunology*; D005260:Female; D007700:Kinetics; D008172:Lung Diseases, Fungal / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D051379:Mice; D008808:Mice, Inbred CBA; D013601:T-Lymphocytes / Q000276:immunology / Q000382:microbiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000502:physiology* / Q000627:therapeutic use
D014409:Tumor Necrosis Factor-alpha