Impact of Distinct Poxvirus Infections on the Specificities and Functionalities of CD4 + T Cell Responses

Abstract

The factors that determine CD4 + T cell (T CD4 + ) specificities, functional capacity, and memory persistence in response to complex pathogens remain unclear. We explored these parameters in the C57BL/6 mouse through comparison of two highly related (>92% homology) poxviruses: ectromelia virus (ECTV), a natural mouse pathogen, and vaccinia virus (VACV), a heterologous virus that nevertheless elicits potent immune responses. In addition to elucidating several previously unidentified major histocompatibility complex class II (MHC-II)-restricted epitopes, we observed many qualitative and quantitative differences between the T CD4 + repertoires, including responses not elicited by VACV despite complete sequence conservation. In addition, we observed functional heterogeneity between ECTV- and VACV-specific T CD4 + at both a global and individual epitope level, particularly greater expression of the cytolytic marker CD107a from T CD4 + following ECTV infection. Most striking were differences during the late memory phase where, in contrast to ECTV, VACV infection failed to elicit measurable epitope-specific T CD4 + as determined by intracellular cytokine staining. These findings illustrate the strong influence of epitope-extrinsic factors on T CD4 + responses and memory. IMPORTANCE Much of our understanding concerning host-pathogen relationships in the context of poxvirus infections stems from studies of VACV in mice. However, VACV is not a natural mouse pathogen, and therefore, the relevance of results obtained using this model may be limited. Here, we explored the MHC class II-restricted T CD4 + repertoire induced by mousepox (ECTV) infection and the functional profile of the responding epitope-specific T CD4 + , comparing these results to those induced by VACV infection under matched conditions. Despite a high degree of homology between the two viruses, we observed distinct specificity and functional profiles of T CD4 + responses at both acute and memory time points, with VACV-specific T CD4 + memory being notably compromised. These data offer insight into the impact of epitope-extrinsic factors on the resulting T CD4 + responses.