title: Impact of distinct poxvirus infections on the specificities and functionalities of CD4+ T cell responses.
abstract: The factors that determine CD4+ T cell (TCD4+) 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 TCD4+ repertoires, including responses not elicited by VACV despite complete sequence conservation. In addition, we observed functional heterogeneity between ECTV- and VACV-specific TCD4+ at both a global and individual epitope level, particularly greater expression of the cytolytic marker CD107a from TCD4+ 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 TCD4+ as determined by intracellular cytokine staining. These findings illustrate the strong influence of epitope-extrinsic factors on TCD4+ responses and memory.
  
  
  OBJECTIVE
  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 TCD4+ repertoire induced by mousepox (ECTV) infection and the functional profile of the responding epitope-specific TCD4+, 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 TCD4+ responses at both acute and memory time points, with VACV-specific TCD4+ memory being notably compromised. These data offer insight into the impact of epitope-extrinsic factors on the resulting TCD4+ responses.
authors: Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors: Nicholas A
authors: NA
authors: Siciliano
authors: Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA Department of Biology, Albright College, Reading, Pennsylvania, USA.
authors: Adam R
authors: AR
authors: Hersperger
authors: Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors: Aimee M
authors: AM
authors: Lacuanan
authors: Fox Chase Cancer Center, Immune Cell Development and Host Defense Program, Philadelphia, Pennsylvania, USA.
authors: Ren-Huan
authors: RH
authors: Xu
authors: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors: John
authors: J
authors: Sidney
authors: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors: Alessandro
authors: A
authors: Sette
authors: Fox Chase Cancer Center, Immune Cell Development and Host Defense Program, Philadelphia, Pennsylvania, USA.
authors: Luis J
authors: LJ
authors: Sigal
authors: Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA Laurence.Eisenlohr@jefferson.edu.
authors: Laurence C
authors: LC
authors: Eisenlohr
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004481:Ectromelia virus / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D005260:Female; D007156:Immunologic Memory; D008810:Mice, Inbred C57BL; D011213:Poxviridae Infections / Q000276:immunology* / Q000821:virology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014616:Vaccinia virus / Q000276:immunology*
chemical_list: D016207:Cytokines; D000939:Epitopes