title: Boosting functional avidity of CD8+ T cells by vaccinia virus vaccination depends on intrinsic T-cell MyD88 expression but not the inflammatory milieu.
abstract: T-cell functional avidity is a crucial determinant for efficient pathogen clearance. Although recombinant DNA priming coupled with a vaccinia-vectored vaccine (VACV) boost has been widely used to mount robust CD8+ T-cell responses, how VACV boost shapes the properties of memory CD8+ T cells remains poorly defined. Here, we characterize the memory CD8+ T cells boosted by VACV and demonstrate that the intrinsic expression of MyD88 is critical for their high functional avidity. Independent of selection of clones with high-affinity T-cell receptor (TCR) or of enhanced proximal TCR signaling, the VACV boost significantly increased T-cell functional avidity through a decrease in the activation threshold. VACV-induced inflammatory milieu is not sufficient for this improvement, as simultaneous administration of the DNA vaccine and mock VACV had no effects on the functional avidity of memory CD8+ T cells. Furthermore, reciprocal adoptive transfer models revealed that the intrinsic MyD88 pathway is required for instructing the functional avidity of CD8+ T cells boosted by VACV. Taking these results together, the intrinsic MyD88 pathway is required for the high functional avidity of VACV-boosted CD8+ T cells independent of TCR selection or the VACV infection-induced MyD88-mediated inflammatory milieu.
  
  
  OBJECTIVE
  Functional avidity is one of the crucial determinants of T-cell functionality. Interestingly, although it has been demonstrated that a DNA prime-VACV boost regimen elicits high levels of T-cell functional avidity, how VACV changes the low avidity of CD8+ T cells primed by DNA into higher ones in vivo is less defined. Here, we proved that the enhancement of CD8+ T cell avidity induced by VACV boost is mediated by the intrinsic MyD88 pathway but not the MyD88-mediated inflammatory milieu, which might provide prompts in vaccine design.
authors.affiliation: Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai, China.
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Hu
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Wan
authors.forename: Lingyan
authors.initials: L
authors.lastname: Zhu
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Ren
authors.forename: Sugan
authors.initials: S
authors.lastname: Qiu
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Ren
authors.forename: Songhua
authors.initials: S
authors.lastname: Yuan
authors.forename: Xiangqing
authors.initials: X
authors.lastname: Ding
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: Chenli
authors.initials: C
authors.lastname: Qiu
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.forename: Jim
authors.initials: J
authors.lastname: Xiang
authors.forename: Chao
authors.initials: C
authors.lastname: Qiu
authors.forename: Jianqing
authors.initials: J
authors.lastname: Xu
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D007117:Immunization, Secondary / Q000379:methods*; D007156:Immunologic Memory; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D012900:Smallpox Vaccine / Q000008:administration & dosage / Q000276:immunology*; D014616:Vaccinia virus / Q000276:immunology*
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012900:Smallpox Vaccine