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The Role of the endoplasmic reticulum in major histocompatibility class II restricted antigen presentation and Immune response

  • Author(s): Wheeler, Matthew Clay
  • et al.
Abstract

The generation of adaptive immune responses requires presentation of major histocompatibility (MHC) class II restricted immunogenic peptides to CD4 T cells by antigen presenting cells (APCs). These peptides are derived from the processing of protein antigens in acidic endosomal compartments. Classically, the generation of such peptides has been thought to have occurred through an exogenous pathway that involves internalization of antigens from the extracellular milieu. Recently, it has been demonstrated that peptides can also be generated from endogenously synthesized and retained antigen. While research in this field is burgeoning the physiological consequences of the processing of intracellular antigen are unknown. This dissertation examines the in vivo consequences and in vitro pathways relevant to the processing and presentation of antigen that is endogenously synthesized and retained in different intracellular compartments by B lymphocytes. I show that peptides derived from the processing of intracellular antigen are able to prime a CD4 T cell response irrespective of intracellular targeting. Furthermore, I show that T cells primed by peptides derived from antigen retained in the endoplasmic reticulum (ER) induce higher secretion of IFN-g and TNFa in responding cells. This increase is associated with upregulation of the ER stress responsive genes GADD34, Grp78 and CHOP, and down regulation of the costimulatory molecule OX40L in B lymphocytes. An OX40L reduced phenotype was recapitulated in CpG activated B lymphocytes by treatment with the ER stress inducing compounds tunicamycin and thapsigargin. I also show that presentation of ER retained antigen is linked to the ER associated degradation (ERAD) pathway. Presentation of the model antigen Ea from an ER targeted IgH requires mannose processing, cytosolic translocation and degradation by the resident cytosolic protease tripeptidyl peptidase II. Additionally, ER stress inducing compounds are able to initiate presentation of a secretory IgH that traffics through the ER but is not normally presented. Ultimately, the research presented here has far reaching implications for immune responses generated under states of cellular stress, such as viral infection oncogenic transformation and anti-idiotype responses at the levels of antigen processing and immune priming. These results reveal important considerations for vaccine design, as ER stress may serve an important adjuvant effect in the induction of cellular immunity

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