Heterologous immunity between viruses

Abstract

Immune memory responses to previously encountered pathogens can sometimes alter the immune response to and the course of infection of an unrelated pathogen by a process known as heterologous immunity. This response can lead to enhanced or diminished protective immunity and altered immunopathology. Here, we discuss the nature of T-cell cross-reactivity and describe matrices of epitopes from different viruses eliciting cross-reactive CD8(+) T-cell responses. We examine the parameters of heterologous immunity mediated by these cross-reactive T cells during viral infections in mice and humans. We show that heterologous immunity can disrupt T-cell memory pools, alter the complexity of the T-cell repertoire, change patterns of T-cell immunodominance, lead to the selection of viral epitope-escape variants, alter the pathogenesis of viral infections, and, by virtue of the private specificity of T-cell repertoires within individuals, contribute to dramatic variations in viral disease. We propose that heterologous immunity is an important factor in resistance to and variations of human viral infections and that issues of heterologous immunity should be considered in the design of vaccines.

Fig. 1. Heterologous immunity between viruses in mice

This figure represents patterns of heterologous immunity between different viruses in C57BL/6 mice. Here, mice immune to one virus, from which the arrow emanates, are challenged with a heterologous virus, toward which the arrow points. The shading of the arrow indicates protective immunity, enhancement of viral titers or no effect. The width of the arrow depicts the relative magnitude of the effect. This figure is based on data from published work (2, 6, 96).

Fig. 2. Potential mechanisms of T-cell-dependent heterologous immunity between viruses

Here the first encountered virus is white and the second encountered virus is black. 1. Direct cross-reactivity between two pathogens, where memory cells specific to the second virus cross-react with antigens of the first virus; 2. Nonspecific activation by cytokines, where the second virus induces cytokines which activate first virus-specific memory cells through cytokines without TCR involvement; 3. Cytokines induced by the second virus plus residual antigen from the persisting original virus trigger the TCR; 4. Activation by self-reactive cellular antigens upregulated by inflammation (IFN) or tissue damage +/− cytokines induced by second virus.

Fig. 3. Cross-reactivity matrices of CD8⁺ T-cell epitopes between viruses defined in our laboratories

(A). Cross-reactivity matrix of K^b-restricted epitopes encoded by LCMV, PV, and VV in C57BL/6 mice. (B). Cross-reactivity matrix of HLA-A2-restricted epitopes between IAV and EBV in humans. Numbers in parentheses represent the numbers of subjects having this cross-reactivity. Width of the lines represents the magnitude of the cross-reactivity when present.

Fig. 4. Implantation of an allogeneic cell line stimulates LCMV-specific memory CD8⁺ T cells to proliferate in vivo

CFSE-labeled splenocytes (3 × 10⁷) from LCMV-immune C57BL6 mice were adoptively transferred into naïve congenic recipient mice, which were inoculated with allogeneic (H2^d) P815 cells 1 day later. Thirteen days after immunization, donor CD8⁺ T cells (CD45.2) from the spleens (A) and the peritoneum (B) of recipient mice were evaluated for division by dilution of CFSE, and the values represent the percentage of CD8⁺ T cells that are CFSE^lo. Recovered splenocytes (A) and peritoneal exudate cells (B) were incubated with either syngeneic (C57BL/6) or allogeneic (BALB/c) splenocytes for 5 h and then evaluated for the production of IFN-γ. Alternatively, recovered splenocytes (C) and peritoneal exudate cells (D) were incubated with the indicated LCMV-encoded peptides for 5 h and then evaluated for the production of IFN-γ. For the intracellular cytokine assays, samples were gated on CD8⁺ cells, and the values shown represent the percentage of either CFSE^lo or CFSE^hi CD8⁺ T cells staining positive for IFN-γ.