PROTECTION AGAINST LETHAL ENCEPHALOMYOCARDITIS VIRUS-INFECTION IN THEABSENCE OF SERUM-NEUTRALIZING ANTIBODIES

Although the ability of serum-neutralizing antibodies to protect again st picornavirus infection is well established, the contribution of cel l-mediated immunity to protection is uncertain. Using major histocompa tibility complex class LI-deficient (RHAP(-/-)) mice, which are unable to mediate CD4(+) T-lymphocyte-dependent humoral responses, we demons trated antibody-independent protection against lethal encephalomyocard itis virus (EMCV) infection in the natural host. The majority of RHAP- /- mice inoculated with 10(4) PFU of attenuated Mengo virus (vMC(24)) resolved infection and were resistant to lethal challenge with the hig hly virulent, serotypically identical cardiovirus, EMCV. Protection in these mice was in the absence of detectable serum-neutralizing antibo dies. Depletion of CD8(+) T lymphocytes prior to lethal EMCV challenge ablated protection in vMC(24)-immunized RHA beta(-/-) mice. The CD8() T-lymphocyte-dependent protection observed in vivo may, in part, be the result of cytotoxic T-lymphocyte (CTL) activity, as CD8+ T splenoc ytes exhibited in vitro cytolysis of EMCV-infected targets. The existe nce of virus-specific CD8(+) T-lymphocyte memory in these mice was dem onstrated by increased expression of cell surface activation markers C D25, CD69, CD71, and CTLA-4 following antigen-specific reactivation in vitro. Although recall response in vMC(24)-immunized RHA beta(-/-) mi ce was intact and effectual shortly after immunization, protection aba ted over time, as only 3 of 10 vMC(24)-immunized RHA beta(-/-) mice su rvived when rechallenged 90 days later. The present study demonstratin g CD8+ T-lymphocyte-dependent protection in the absence of serum-neutr alizing antibodies, coupled with our previous results indicating that vMC(24)-specific CD4(+) T lymphocytes confer protection against lethal EMCV in the absence of prophylactic antibodies, suggests the existenc e of nonhumoral protective mechanisms against picornavirus infections.