Abstract
Major histocompatibility complex class II (MHCII) proteins are loaded with endosomal peptides and reside at the surface of antigen-presenting cells (APCs) for a time before being degraded. In vitro, MHCII protein levels and turnover are affected by peptide loading and by rates of ubiquitin-dependent internalization from the cell surface, which is in turn affected by APC type and activation state. Prior work suggested that fast turnover of disease-associated MHCII alleles may contribute to autoimmunity. We recently developed novel stable isotope tracer techniques to test this hypothesis in vivo. In non-obese diabetic (NOD) mice, a model of type 1 diabetes (T1D), MHCII turnover was affected by APC type, but unaffected by disease-associated structural polymorphism. Differences in MHCII turnover were observed between NOD colonies with high and low T1D incidence, but fast turnover was dispensable for autoimmunity. Moreover, NOD mice with gene knockouts of peptide loading cofactors do not develop T1D. Thus, fast turnover does not appear pathogenic, and conventional antigen presentation is critical for autoimmunity in NOD mice. However, shared environmental factors may underpin colony differences in MHCII protein turnover, immune regulation, and pathogenesis.
Highlights
Major histocompatibility complex class II (MHCII) molecules present peptides at cell surfaces for recognition by CD4+ T lymphocytes
We describe recent methodological advances in measuring MHCII protein turnover in vivo, which enabled us to examine the postulated role of MHCII protein turnover in autoimmune pathogenesis in a mouse model
DETERMINANTS OF MHCII PROTEIN TURNOVER Major histocompatibility complex class II degradation in nonactivated dendritic cells (DCs) begins with internalization from the cell surface, which is triggered by ubiquitination of the cytoplasmic tail of the MHCII β chain [10] by the ubiquitin E3 ligase, membraneassociated RING-CH 1 (MARCH-1) [11, 12]
Summary
Major histocompatibility complex class II (MHCII) molecules present peptides at cell surfaces for recognition by CD4+ T lymphocytes. They shape a functional, self-tolerant T-cell repertoire via positive and negative thymocyte selection and support peripheral CD4+ T-cell homeostasis [1]. FUNCTIONAL SIGNIFICANCE OF MHCII PROTEIN TURNOVER Major histocompatibility complex class II proteins are expressed constitutively by antigen-presenting cells [APCs: B cells, dendritic cells (DCs), macrophages, thymic epithelial cells] and inducibly by other cell types. DETERMINANTS OF MHCII PROTEIN TURNOVER Major histocompatibility complex class II degradation in nonactivated DCs begins with internalization from the cell surface, which is triggered by ubiquitination of the cytoplasmic tail of the MHCII β chain [10] by the ubiquitin E3 ligase, membraneassociated RING-CH 1 (MARCH-1) [11, 12]. The serine protease, Cathepsin G, cleaves MHCII molecules at a specific membrane-proximal site in vitro, www.frontiersin.org
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