Low-Level MHC Class II Expression Leads to Suboptimal Th Cell Response, Increased Autoaggression, and Heightened Cytokine Inducibility

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-A , 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-A and I-A 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-A mice, transfer of I-A CD25 CD4 T cells into RAG-knockout hosts revealed increased autoaggression activity against the liver. Compared to I-A mice, infection of I-A mice with graded doses of 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-A mice previously infected with a relative low dose of CD44 CD4 T cells from I-A and I-A mice previously infected with a relatively high dose displayed highly similar Ag-specific multicytokine production profiles. In contrast, polyclonal activation of endogenous memory-like I-A CD44 CD4 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-A 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.