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. 1998 Oct;72(10):8052-60.
doi: 10.1128/JVI.72.10.8052-8060.1998.

Protection against lethal encephalomyocarditis virus infection in the absence of serum-neutralizing antibodies

Z C Neal  1 , G A Splitter
Affiliations

Protection against lethal encephalomyocarditis virus infection in the absence of serum-neutralizing antibodies

Z C Neal et al. J Virol. 1998 Oct.

Abstract

Although the ability of serum-neutralizing antibodies to protect against picornavirus infection is well established, the contribution of cell-mediated immunity to protection is uncertain. Using major histocompatibility complex class II-deficient (RHAbeta-/-) mice, which are unable to mediate CD4(+) T-lymphocyte-dependent humoral responses, we demonstrated antibody-independent protection against lethal encephalomyocarditis virus (EMCV) infection in the natural host. The majority of RHAbeta-/- mice inoculated with 10(4) PFU of attenuated Mengo virus (vMC24) resolved infection and were resistant to lethal challenge with the highly virulent, serotypically identical cardiovirus, EMCV. Protection in these mice was in the absence of detectable serum-neutralizing antibodies. Depletion of CD8(+) T lymphocytes prior to lethal EMCV challenge ablated protection in vMC24-immunized RHAbeta-/- 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 splenocytes exhibited in vitro cytolysis of EMCV-infected targets. The existence of virus-specific CD8(+) T-lymphocyte memory in these mice was demonstrated by increased expression of cell surface activation markers CD25, CD69, CD71, and CTLA-4 following antigen-specific reactivation in vitro. Although recall response in vMC24-immunized RHAbeta-/- mice was intact and effectual shortly after immunization, protection abated over time, as only 3 of 10 vMC24-immunized RHAbeta-/- mice survived when rechallenged 90 days later. The present study demonstrating CD8(+) T-lymphocyte-dependent protection in the absence of serum-neutralizing antibodies, coupled with our previous results indicating that vMC24-specific CD4(+) T lymphocytes confer protection against lethal EMCV in the absence of prophylactic antibodies, suggests the existence of nonhumoral protective mechanisms against picornavirus infections.

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Figures

FIG. 1
FIG. 1
Susceptibility of RHAβ−/− mice to vMC24-induced lethal disease. Naive mice (strains C57BL/6, β2m−/−, and RHAβ−/−) were inoculated i.p. with 102 (■), 104 (•), or 108 (▴) PFU of live EMCV or 102 (□), 104 (○), or 108 (▵) PFU of live vMC24 on day 0. Mice were monitored for development of lethal cardiovirus disease during the following 28 days. The data are representative of three experiments.
FIG. 2
FIG. 2
Lethal EMCV challenge of vMC24-immunized RHAβ−/− mice. Naive mice (strains C57BL/6, β2m−/−, and RHAβ−/−) were immunized i.p. with 104 PFU of live vMC24. On day 21 postimmunization, surviving mice were lethally challenged with 104 PFU of EMCV i.p. and monitored for development of lethal cardiovirus disease. Nonimmune controls were similarly challenged on day 21. Data are representative of four experiments.
FIG. 3
FIG. 3
In vivo T-lymphocyte subset depletion. Naive mice (strains C57BL/6, β2m−/−, and RHAβ−/−) were immunized i.p. with 104 PFU of vMC24 and lethally challenged with 104 PFU of EMCV i.p. on day 21 postimmunization. In some instances, immune mice were depleted of CD4+ or CD8+ T lymphocytes by using antibody therapy prior to lethal challenge as described in Materials and Methods. Depletions resulted in >98% reduction of specific T-lymphocyte subpopulations in vivo. Some nonimmune controls received 500 μl of immune serum (titer of >2,048) intravenously 24 h prior to challenge. Data are representative of three experiments.
FIG. 4
FIG. 4
Cytolytic activity of vMC24-immune RHAβ−/− splenocytes. vMC24-immune splenocytes were cultured with live vMC24 (A) or EMCV (B) and used as effector cells at various ratios in CTL assays with 51Cr-labeled EMCV-infected MC57 target cells. In some instances, the population of effector cells was depleted of CD8+ cells prior to CTL assay. Depletions were >97% effective, as determined by flow cytometry. The data are representative of three experiments.
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