T-CELL SOURCE OF TYPE-1 CYTOKINES DETERMINES ILLNESS PATTERNS IN RESPIRATORY SYNCYTIAL VIRUS-INFECTED MICE

Manipulation of the cytokine microenvironment at the time of vaccinati on can influence immune responses to remote challenge, providing a str ategy to study the molecular pathogenesis of respiratory syncytial vir us (RSV) vaccine-enhanced disease in the mouse model. Although treatme nt with antibody against IL-4 or recombinant IL-12 (rIL-12) at the tim e of formalin-inactivated RSV vaccination induced a similar shift in t he pattern of cytokine mRNA expression upon live virus challenge, anti -IL-4 treated mice had increased CD8(+) cytotoxic T lymphocyte activit y and reduced illness compared with rIL-12-treated mice. To define eff ector mechanisms responsible for these patterns, CD4(+) and/or CD8(+) T lymphocytes were selectively depleted in vivo at the time of RSV cha llenge. In rIL-12-treated mice, CD4(+) lymphocytes made the largest co ntribution to IFN-gamma mRNA, RSV clearance, and illness, while in ant i-IL-4 treated mice, CD8(+) lymphocytes were the major effector. The e ffector responsible for virus clearance also mediated illness, suggest ing that efficiency of virus clearance determined disease expression. These results demonstrate that the phenotype of effector cells involve d in the immune response to virus challenge may be a more important de terminant of disease than patterns of cytokine expression classically assigned to Th1 and Th2 lymphocytes.