The immunological resistance of a host to viral infections may be strongly influenced by cytokines such as interleukin-12 (IL-12) and gamma interferon (IFN-␥), which promote T helper type 1 responses, and IL-4, which promotes T helper type 2 responses. We studied the role of these cytokines during primary and secondary immune responses against Friend retrovirus infections in mice. IL-4-and IL-12-deficient mice were comparable to wild-type B6 mice in the ability to control acute and persistent Friend virus infections. In contrast, more than one-third of the IFN-␥-deficient mice were unable to maintain long-term control of Friend virus and developed gross splenomegaly with high virus loads. Immunization with a live attenuated vaccine virus prior to challenge protected all three types of cytokine-deficient mice from viremia and high levels of spleen virus despite the finding that the vaccinated IFN-␥-deficient mice were unable to class switch from immunoglobulin M (IgM) to IgG virus-neutralizing antibodies. The results indicate that IFN-␥ plays an important role during primary immune responses against Friend virus but is dispensable during vaccine-primed secondary responses.

No abstract

CD4؉ Th1 responses to virus infections are often necessary for the development and maintenance of virus-specific CD8 ؉ T-cell responses. However, in the present study with Friend murine retrovirus (FV), the reverse was also found to be true. In the absence of a responder H-2 b allele at major histocompatibility complex (MHC) class II loci, a single H-2D Recovery from virus infections often requires the development of both cell-mediated and humoral immune responses which are regulated by CD4 ϩ helper T cells. CD4 ϩ helper T cells have been divided into two major functional types, Th1 and Th2. Th1 cells have an integral role in protective immunity against virus infections, providing help for the development and maintenance of both cytotoxic T lymphocyte (CTL) and neutralizing antibody responses and also directly suppressing virus replication by the secretion of gamma interferon (IFN-␥) (5,23,43). Th2 responses also provide help for the generation of neutralizing antibody responses but can suppress the development of antiviral Th1 responses through the production of immunosuppressive cytokines like interleukin-10 (IL-10) and/or transforming growth factor ␤ (TGF-␤) (8, 36). Thus, protection against retrovirus infection which requires both cellmediated and humoral effector mechanisms (19) may be favored by the development of a Th1 rather than a Th2 CD4 ϩ T-cell response.Although many factors can direct CD4 ϩ T cells toward a Th1 or Th2 response (9), the regulation of these responses during infection in vivo is not well understood. One factor that has been shown to affect the development of CD4 ϩ Th1 or Th2 responses in vivo is the major histocompatibility complex (MHC) genotype of the host (34). In fact, MHC regulation of these responses can influence whether or not a host recovers from infection with a specific pathogen (2,22). This has been best studied in mice, where the MHC genotypes of inbred strains can determine resistance or susceptibility to infection (28,43). mice is dependent upon the generation of strong immune responses, including FV-specific CD8 ϩ CTLs, neutralizing antibody, and CD4 ϩ T cells (19). The present study examined the effects of different subregions of MHC on FV-specific CD4 ϩ T-cell subsets. As expected, an FV-specific Th1 response was associated with MHC class II genes of the H-2 b haplotype, since MHC class II molecules present peptides which are antigenic to CD4 ϩ T cells (33,35). However, in the absence of H-2 b alleles at the MHC class II loci, a strong FV-specific Th1 response was also associated with an H-2 b allele at the MHC class I locus, H-2D. This surprising effect was mediated by CD8 ϩ T cells, which appeared to exert a helper effect on the CD4 ϩ T-cell response to this virus.