title: Antigen signal strength during priming determines effector CD4 T cell function and antigen sensitivity during influenza virus challenge.
abstract: TCR signal strength during priming is a key determinant of CD4 T cell activation, but its impact on effector CD4 T functions in vivo remains unclear. In this study, we compare the functionality of CD4 T cell responses induced by peptides displaying varying binding half-lives with MHC class II before and after influenza virus infection. Although significant quantitative and qualitative differences in CD4 T cell responses were observed before infection between mice vaccinated with low- or high-stability peptides, both mice mounted robust early Th1 effector cytokine responses upon influenza challenge. However, only effector CD4 T cells induced by low-stability peptides proliferated and produced IL-17A after influenza challenge. In contrast, effector T cells elicited by higher-stability peptides displayed a terminally differentiated phenotype and divided poorly. This defective proliferation was T cell intrinsic but could not be attributed to a reduced expression of lymph node homing receptors. Instead, we found that CD4 T cells stimulated with higher-stability peptides exhibited decreased responsiveness to low levels of Ag presentation. Our study reveals the critical role of TCR signal strength during priming for the function and Ag sensitivity of effector CD4 T cells during viral challenge.
authors.affiliation: BloodCenter of Wisconsin, Blood Research Institute, Milwaukee, WI 53226; Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226;
authors.forename: Mika
authors.initials: M
authors.lastname: Nagaoka
authors.affiliation: Department of Pathobiological Sciences, Influenza Research Institute, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53711; FluGen, Madison, WI 53711; and.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Hatta
authors.affiliation: Department of Pathobiological Sciences, Influenza Research Institute, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53711; Division of Virology, Department of Microbiology and Immunology, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
authors.affiliation: BloodCenter of Wisconsin, Blood Research Institute, Milwaukee, WI 53226; Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226; laurent.malherbe@bcw.edu.
authors.forename: Laurent P
authors.initials: LP
authors.lastname: Malherbe
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D017951:Antigen Presentation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D020381:Interleukin-17 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009975:Orthomyxoviridae / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*
chemical_list: C098680:Il17a protein, mouse; D020381:Interleukin-17; D011948:Receptors, Antigen, T-Cell
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