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 Cr yptococcus neoformans infection (via the recruitment and activation of inflammatory cells), The objective of our studies was to determine wh ether TNF-alpha is required during the afferent phase of the response, The levels of TNF-alpha mRNA and protein in the lungs increased follo wing intratracheal inoculation of CBA/J mice with C, neoformans 52 and preceded the development of an inflammatory response in the lungs, Ad ministration of neutralizing TNF-alpha-specific antiserum on days 0, 3 , 6, and 9 reduced inflammatory cell recruitment by 80% on day 13, res ulting in a S-fold increase in lung C, neoformans CFU, The number of C D4(+) T cells was decreased by 65%, the number of neutrophils was decr eased by 84%, and the number of macrophages was decreased by >98%, Str ikingly, a single dose of neutralizing anti-TNF-alpha serum was suffic ient to prevent the development of protective cell-mediated immunity o n day 35 if administered on day 0, but was ineffective if delayed unti l day 14, Day 0 anti-TNF-alpha-treated mice could not generate cryptoc occus-specific delayed type hypersensitivity reactivity, clear the inf ection from their lungs (10(4)-fold increase in CFU), control dissemin ation to the spleen and brain (10(5)- and 10(6)-fold increases in CFU) , or adoptively transfer cryptococcus-specific immunity (mononuclear c ell recruitment into the lungs following intratracheal challenge or fo otpad delayed type hypersensitivity). Thus, the production of TNF-alph a during the afferent phase of the immune response against a pulmonary C, neoformans infection (before day 14) is critical for the developme nt of protective T cell immunity in both the lungs and extrapulmonary sites.