Beta 2-microglobulin-, CD8+ T-cell-deficient mice survive inoculation with high doses of vaccinia virus and exhibit altered IgG responses.

Abstract

Transgenic mice lacking an intact P2-microglobulin (J32m) gene fail to express major histocompatibility complex (MHC) class I proteins on the cell surface and, as a result, are virtually devoid of CD4-CD8+ lymphocytes. These animals provide a unique model system for directly assessing the role of CD8+ lymphocytes in the modulation of viral infection in vivo. P2m_ CD8-mice and their normal littermates were inoculated at the base of the tail with the WR strain of vaccinia virus and monitored for serum antibody and lesion formation. Both groups developed similar lesions in response to a broad virus dose range, and all animals had completely recovered by day 28 after inoculation. Isotypespecifi immunogibulin levels were determined for each animal on day 7 and day 14 after primary inoculation, and again 7 days after a virus challenge. The virus-specific IgG1, IgG2a, and IgG2b levels were signifcantly different in the (2m-/-group (20-, 9-, and 30-fold lower, respectively, on day 7 after challenge) compared with the f2m+ /-group. Virus-specific serum IgM levels for both groups remained similar throughout the experiment. In a separate experiment, 32m-/-mice were immunized with a nonviral antigen, 2,4,6-trinitrophenylconjugated keyhole limpet hemocyanin, and both total and antigen-specific isotype-specific immunoglobulin titers were determined. Total IgG1, IgG2a, IgG2b, and IgG3 tended to be iower overall in the f2m-/-mice compared with j82m+/-littermates. In contrast, total and antigen-specific IgE titers were similar in the two groups. These data indicate that CD81 lymphocytes are not required to clear high doses of vaccinia virs, and they suggest that f21m/-mice are less efficient at antigen-specific IgG production than their (3m+/-littermates.

Cellular and Humoral Immunity against Vaccinia Virus Infection of Mice

“…Kinetic analysis of VV-specific T cell responses in BALB/c mice have shown that VV infection can induce a potent primary CD8 ϩ T cell response as well as long-term memory (15). However, ␤2m Ϫ/Ϫ mice almost completely lacking CD8 ϩ T cells survived high-dose s.c. infection with similar lesion development as control mice (16). In addition, absence of either perforin-or Fas-dependent cytotoxicity did not affect clearance of a primary VV infection (17).…”

“…Spriggs et al (16) showed that ␤2m Ϫ/Ϫ mice, which lack CD8 T cells, survived infection with high virus doses similar to those of control mice. In this report, the course of infection appeared indistinguishable from controls except that less virus-specific IgG Abs were produced.…”

Human Cytotoxic CD4+ T Cells Recognize HLA-DR1-Restricted Epitopes on Vaccinia Virus Proteins A24R and D1R Conserved among Poxviruses

“…Studies of VV-specific T cell responses in BALB/c mice have shown that VV infection induces a potent primary CD8 ϩ T cell response as well as long-term memory (43). However, ␤ 2 -microglobulin Ϫ/Ϫ mice almost completely lacking CD8 ϩ T cells survived high-dose s.c. infection with similar lesion development as control mice (44). In addition, studies in mice show that the absence of either perforin-or Fas-dependent cytotoxicity did not affect clearance of a primary VV infection (45).…”

JE-ADVAX Vaccine Protection against Japanese Encephalitis Virus Mediated by Memory B Cells in the Absence of CD8+T Cells and Pre-Exposure Neutralizing Antibody

“…The widely accepted correlate of clinical efficacy for JE vaccines is a neutralizing antibody titer of Ն10 determined in vitro in the PRNT 50 assay (24)(25)(26). However, ␤ 2 m Ϫ/Ϫ mice, in addition to their lack of CD8 ϩ T cells, are unable to produce long-lived IgG antibodies after viral or model antigen exposure (18,(27)(28)(29). The latter is the result of a deficiency of the neonatal Fc receptor (FcRn) in these mice.…”