title: Low-Level MHC Class II Expression Leads to Suboptimal Th Cell Response, Increased Autoaggression, and Heightened Cytokine Inducibility.
abstract: The development and activation of MHC class II (MHC-II)-restricted CD4+T cells are distinct immunological processes that are strictly MHC-II-dependent. To address their relative dependence on MHC-II, we established a novel ENU-induced mutant mouse on the C57BL/6 background, named I-A12%, with ∼8-fold reduced I-A expression on the surface of B cells, dendritic cells, cortical thymic epithelial cells, and medullary thymic epithelial cells. I-A100%and I-A12%mice are highly similar with respect to the numbers of double-positive thymocytes, CD4+CD8-T cells, regulatory T cells, CD4+T cell marker expression, lifespan, and Th/regulatory T cell function. Despite the demonstration of functional intrathymic negative selection in I-A12%mice, transfer of I-A12%CD25-CD4+T cells into RAG-knockout hosts revealed increased autoaggression activity against the liver. Compared to I-A100%mice, infection of I-A12%mice with graded doses ofListeria monotcytogenesor influenza virus revealed comparable and significantly reduced generation of Ag-specific CD4+T cells at high and low infection doses, respectively. A significantly weakened Ag-specific recall cytokine production response was also found for I-A12%mice previously infected with a relative low dose ofL. monocytogenesCD44hiCD4+T cells from I-A100%and I-A12%mice previously infected with a relatively highL. monocytogenesdose displayed highly similar Ag-specific multicytokine production profiles. In contrast, polyclonal activation of endogenous memory-like I-A12%CD44hiCD4+T cells revealed highly elevated production of multiple cytokines. Our results demonstrate that there exist distinct thresholds for different MHC-II-dependent immunological processes. The I-A12%mutant mouse model we describe in the present study is a valuable tool for investigations on the quantitative cause-effect relationship in MHC-II-dependent normal and autoimmune responses.
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Chen
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Yu-Chia
authors.initials: YC
authors.lastname: Su
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Chang
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Pi-Fang
authors.initials: PF
authors.lastname: Tsai
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan mbkung@ccvax.sinica.edu.tw.
authors.forename: John T
authors.initials: JT
authors.lastname: Kung
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D005802:Genes, MHC Class II; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007156:Immunologic Memory; D008089:Listeria monocytogenes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009975:Orthomyxoviridae / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013950:Thymus Gland / Q000033:anatomy & histology / Q000166:cytology / Q000276:immunology*
chemical_list: D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D016693:Receptors, Antigen, T-Cell, alpha-beta