Disparate Epitopes Mediating Protective Heterologous Immunity to Unrelated Viruses Share Peptide–MHC Structural Features Recognized by Cross-Reactive T Cells

Abstract

Closely related peptide epitopes can be recognized by the same T cells and contribute to the immune response against pathogens encoding those epitopes, but sometimes cross-reactive epitopes share little homology. The degree of structural homology required for such disparate ligands to be recognized by cross-reactive T cell receptors remains unclear. Here, we examined the mechanistic basis for cross-reactive T cell responses between epitopes from unrelated and pathogenic viruses, lymphocytic choriomeningitis virus (LCMV) and vaccinia virus (VV). Our results show that the LCMV-cross-reactive T cell response towards VV is dominated by a shared asparagine residue, together with other shared structural elements conserved in the crystal structures of Kb-VV-A11R and Kb-LCMV-GP34. Based on analysis of the crystal structures and the specificity determinants for the cross-reactive T cell response, we were able to manipulate the degree of cross-reactivity of the T cell response, and to predict and generate a LCMV-cross-reactive response towards a variant of a null ovalbumin-derived peptide. These results indicate that protective heterologous immune responses can occur for disparate epitopes from unrelated viruses.

Vaccination and heterologous immunity: educating the immune system

“…23,24,27,28,34,[54][55][56] Furthermore, structural studies on crossreactivity between LCMV and VACV epitopes can pinpoint the target of crossreactivity and render the OVA SIINFEKL epitope crossreactive with LCMV by an amino acid substitution. 57,58 Crossreactivity is an essential feature of TCR, and the positive selection of T cells in the thymus is mediated through self-peptides that crossreact with a substantial repertoire of foreign epitopes.…”

“…[57][58][59][60] In a T cell repertoire, that which is common between individuals, be it TCR VA usage or a common amino acid sequence or 'motif', is a public specificity; that which is different between individuals, such as a CDR3 sequence, is a 'private' specificity. Thus, genetically identical hosts have, as a consequence of random DNA recombination events, genetically different immune systems, and this diversity of TCR usage poses a challenge when one considers whether an epitope-specific T cell response may be crossreactive with another epitope.…”

“…LCMV and VACV share a complex matrix of CD8 T cell crossreactivity, which has been defined and studied molecularly. 28,52,57 Herein, adoptive transfer studies showed that T cell private specificity of crossreactive memory responses plays a major role in the protection and immunopathology. 32,33 The IAV+LCMV respiratory infection mouse model is noteworthy in that there are both higher titers of LCMV and much greater lung pathology in mice previously infected with IAV, both detrimental effects of heterologous immunity.…”

The Possible Collisions in Virus Infection Immunodiagnostics and Vaccination

“…Гетерологичный иммунный ответ может также обусловливать отторжение транспланта-тов и предрасположенность к возникновению аутоиммунных болезней при перенесении неко-торых инфекций. В частности, он может разру-шить пул Т-клеток памяти, изменить сложность Т-клеточного репертуара, изменить паттерны Т-клеточной иммунодоминантности, привести к селекции вариантов вирусных эпитопов, избе-гающих иммунное узнавание, изменить патоге-нез вирусной инфекции и специфику ее проте-кания, изменить необходимость в определенных цитокинах для контроля инфекции [10,11,12,16].…”

Evaluation of non-reciprocal heterologous immunity between unrelated viruses

“…Subsets of T cells specific to each of these three LCMV epitopes cross-react with a single VACV epitope, A11R 198–205, and A11R 198–205 -specific T cell lines from LCMV-immune mice can bind to both VACV A11R 198–205 and LCMV GP 118–125 or GP 34–41 tetramers (Cornberg et al, 2010). Structural studies defining the nature of cross-reactivity have been done between the LCMV GP 34–41 and the VACV A11R 198–205 epitopes (Z. T. Shen et al, 2013), and GP 34–41 /A11R 198–205 cross-reactive cell lines proliferate in response to VACV infection in vivo and provide protective immunity (Cornberg et al, 2010). It should be pointed out, however, that this type of cross-reactive response is not seen in all mice.…”