Systemic Lupus Erythematosus MHC Class I Family Proteins Retard

Dysregulation of the T cell-dependent Ab response can lead to numerous immunological disorders, ranging from systemic lupus erythematosus to B cell lymphomas. Cellular processes governed by MHC class II proteins play a major role in this response and its dysregulation. The extent to which processes controlled by the diverse family of MHC class I proteins impact such autoimmune and neoplastic disorders, however, is less clear. In this study, we genetically dissect the contributions of individual MHC class I family members and the pathological processes under their control in the systemic lupus erythematosus-like disease of BXSB.Yaa mice and B cell lymphomagenesis of SJL mice. This study reveals a powerful repressive regulatory axis comprised of MHC class I-dependent CD8 + T cells and NK cells. These results indicate that the predominant role of the MHC class I protein family in such immunological disorders is to protect from more aggressive diseases. T he T cell-dependent Ab response is the culmination of multiple cellular and receptor interactions that result in high-affinity Ag-specific IgG Abs and long-term memory. Optimally, this response is finely tuned to maximize immunity while minimizing collateral damage to the host. However, dysregulation of the response can lead to the development of a spectrum of immunological disorders including the prototypic autoantibody-dependent disease, systemic lupus erythematosus (SLE), as well as B cell lymphomas of germinal center (GC) and post-GC origin. Proteins encoded by the MHC play important roles in both normal and autoimmune responses. MHC class II proteins are essential because they present processed peptides on APCs that are required to stimulate Ag-specific CD4 + T cells that drive B cells to mature and secrete IgG Abs as well as supporting CD4 + regulatory T cells (T regs) that have suppressor functions (reviewed in Ref. 1). Less is known regarding the extent to which MHC class I proteins significantly impact these responses. The MHC class I protein family is large and diverse, and most members require association with the b 2-microglobulin (B2M) chain for their cell-surface expression and function. The highly polymorphic, classical MHC class Ia proteins present a vast array of processed peptides and are critical for the development of CD8 + T cells and their TCR repertoire, which is required for discrimination between self and nonself. MHC class Ia proteins also serve as ligands for inhibitory innate receptors on NK cells. The minimally polymorphic MHC class 1b proteins serve both overlapping …