Pathological features of heterologous immunity are regulated by the private specificities of the immune repertoire

Abstract

Heterologous immunity associated with cross-reactive T-cell responses is proposed to contribute to variations among individuals in the pathogenesis of human viral infections. In genetically identical mice with similar infection histories, marked variations in the magnitude and specificities of T-cell responses under conditions of heterologous immunity occur and have been linked to the private specificity of T-cell repertoires in individual immune mice. Variations in immunopathology in the form of panniculitis are observed in lymphocytic choriomeningitis virus-immune mice after vaccinia virus infection. By adoptively transferring splenocytes from individual lymphocytic choriomeningitis virus-immune donors into paired recipients, we show here that, on vaccinia virus infection, similar levels of panniculitis were generated in recipients from a single donor, but the severity of panniculitis varied among recipients receiving cells from different donors. This indicates that virus-induced immunopathology under conditions of heterologous immunity is a function of the private specificity of the immune repertoire.

Figure 1

Variable levels of panniculitis independent of VV load in genetically identical LCMV-immune mice during acute VV infection. LCMV-immune (A and B) and nonimmune (C and D) mice were challenged with VV i.p. At day 6 of infection, the levels of panniculitis were recorded, and VV loads in fat-pads were assayed. A and C: different levels of panniculitis developed after VV challenge: LCMV-immune = 2.9 ± 0.2 versus naïve = 1.2 ± 0.2; P < 0.0001 by Mann Whitney test. No correlation between VV loads and levels of panniculitis were found in either LCMV-immune (B) or nonimmune (D) mice.

Figure 2

Variations in panniculitis in VV-infected LCMV-immune mice determined by the private nature of the immune T-cell repertoire. A and C: Pooled LCMV-immune cells derived from multiple Ly5.1 LCMV-immune donors were transferred into four or five naïve Ly5.2 mice, which were examined at day 6 of VV infection. A shows the levels of panniculitis from three independent experiments, where enriched CD3+ spleen T cells were transferred in Experiments (Exp) 1 and 2 and unfractionated spleen leukocytes were transferred in Exp 3, as described in Materials and Methods. C: the fold changes of LCMV-specific T cell responses, as detected by peptide-induced intracellular IFN-γ assay after subtracting background. The percentages of donor epitope-specific responses per CD8 cell before adoptive transfer in B and C are indicated in parentheses. B and D: LCMV-immune cells derived from a single donor were transferred equally into two congenic hosts. At day 6 of VV infection, LCMV-specific responses of donor cells isolated from PEC were examined by intracellular cytokine assay, and the levels of panniculitis were evaluated. The fold changes of LCMV-specific responses are shown in B, which presents data from Exp 4 of Table 1. Pictures of fat-pads from two representative pairs of mice are shown in D.