Private specificities of CD8 T cell responses control patterns of heterologous immunity

Kim, Sung-Kwon; Cornberg, Markus; Wang, Xiaoting Z.; Chen, Hong D.; Selin, Liisa K.; Welsh, Raymond M.

Mouse models have shown that a history of a heterologous virus infection can alter the kinetics and the hierarchy of T cells responding to peptide epitopes encoded by the infecting virus, and this skewing of T cell responsiveness may be either beneficial or harmful to the host (2, 6) . Any foreign protein is likely to have several amino acid epitope sequences with appro-priate motifs to engage a given MHC molecule, but the T cell response to a virus infection is usually focused against a narrow subset of these potential epitopes. This is a consequence of T cell immunodominance, which is a very fickle phenomenon. If immunodominant epitopes are experimentally deleted from a pathogen, other epitopes almost invariably emerge to dominate the response (9) . This is either because they become presented better at the MHC level or because they stimulate T cells whose initial frequencies were lower than the originally immunodominant ones (9) . T cell immunodominance can be dramatically affected by a prior infection with a pathogen that encodes an epitope that generates T cells that cross-react with a second pathogen (2) . For example, lymphocytic choriomeningitis virus (LCMV) and Pichinde virus (PV) each encode weak subdominant epitopes with six out of eight amino acids in common. Some T cells can cross-react between those epitopes, and when a host immune to one of those viruses is infected with the other, this weak epitope now dominates the T cell response, and the normally dominant epitopes generate much weaker responses. The higher frequencies of memory T cells specific to this cross-reactive epitope as compared with naive T cells specific to the normally dominant epitopes gives an advantage for proliferative expansion. Similarly, individuals immune to one dengue virus serotype on infection with a second serotype tend to generate T cell responses that better recognize the first serotype, presumably because they were expanded from the memory pool (8) . It is noteworthy that this deviation in T cell responses during dengue infections is associated with serious pathological complications.