Low-Level MHC Class II Expression Leads to Suboptimal Th Cell Response, Increased Autoaggression, and Heightened Cytokine Inducibility
| Autor: | Mei-Ling Chang, John T. Kung, Pi-Fang Tsai, Yi-Ting Chen, Yu-Chia Su |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
CD4-Positive T-Lymphocytes
0301 basic medicine Regulatory T cell Receptors Antigen T-Cell alpha-beta medicine.medical_treatment T cell Genes MHC Class II Immunology Thymus Gland CD8-Positive T-Lymphocytes Biology T-Lymphocytes Regulatory Mice 03 medical and health sciences Interleukin 21 0302 clinical medicine Antigen medicine Animals Immunology and Allergy Cytotoxic T cell Mice Knockout MHC class II Histocompatibility Antigens Class II T-Lymphocytes Helper-Inducer Orthomyxoviridae Listeria monocytogenes Mice Inbred C57BL 030104 developmental biology Cytokine medicine.anatomical_structure biology.protein Cytokines Immunologic Memory CD8 030215 immunology |
| Zdroj: | The Journal of Immunology. 198:1928-1943 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1600967 |
| Popis: | 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 of Listeria monotcytogenes or 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 of L. monocytogenes. CD44hiCD4+ T cells from I-A100% and I-A12% mice previously infected with a relatively high L. monocytogenes dose 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. |
| Databáze: | OpenAIRE |
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