T cell cross-reactivity between different strains of the same virus, between different members of the same virus group, and even between unrelated viruses is a common occurrence. We questioned here how an intervening infection with a virus containing a sub-dominant cross-reactive T cell epitope would affect protective immunity to a previously encountered virus. Pichinde virus (PV) and lymphocytic choriomeningitis virus (LCMV) encode subdominant cross-reactive NP(205-212) CD8 T cell epitopes sharing 6 of 8 amino acids, differing only in the MHC anchoring regions. These pMHC epitopes induce cross-reactive but non-identical T cell receptor (TCR) repertoires, and structural studies showed that the differing anchoring amino acids altered the conformation of the MHC landscape presented to the TCR. PV-immune mice receiving an intervening infection with wild type but not NP205-mutant LCMV developed severe immunopathology in the form of acute fatty necrosis on re-challenge with PV, and this pathology could be predicted by the ratio of NP205-specific to the normally immunodominant PV NP(38-45) -specific T cells. Thus, cross-reactive epitopes can exert pathogenic properties that compromise protective immunity by impairing more protective T cell responses.
Chen, A. T., Cornberg, M., Gras, S., Guillonneau, C., Rossjohn, J., Trees, A., Emonet, S., de la Torre, J. C., Welsh, R. M., & Selin, L. K. (2012). Loss of anti-viral immunity by infection with a virus encoding a cross-reactive pathogenic epitope. PLoS Pathogens, 8(4 (Art. ID: e1002633)), 1 - 12. https://doi.org/10.1371/journal.ppat.1002633