The long term goal of our research is to understand and manipulate immune surveillance pathways. The antigen processing mechanisms yields thousands of peptide/MHC complexes (pMHC I and pMHC II) on the cell surface as potential ligands for CD8+ and CD4+ T cells respectively. With prior funding support we showed that antigenic peptides are trimmed not only in the cytoplasm, but also in the endoplasmic reticulum by ERAAP, the ER aminopeptidase associated with antigen processing. This key concept is now part of current text book descriptions of antigen processing pathways. In ERAAP-deficient mice, lack of peptide trimming in the ER has been found to disrupt the normal peptide repertoire by both classic MHC Ia as well as non-classical MHC Ib molecules: many pMHC I are missing and numerous novel pMHC I emerge on the surface of ERAAP-deficient cells. The loss and gain of unique peptides results in vigorous reciprocal immune responses in wild-type versus ERAAP-deficient mice. We have also discovered that ERAAP and MHC I interact physically and functionally and truncated ERAAPdomains serve as dominant negative regulators of MHC I peptide presentation. Unexpectedly, we also discovered that ERAAP can also regulate peptide presentation by MHC class II molecules and hence CD4 T cell responses as well. These properties of ERAAP may explain the recent genome wide association studies that have shown that polymorphic variants of ERAP1 (human ortholog of mouse ERAAP) are associated with autoimmune diseases such as ankylosing spondylitis and psoriasis. Here we will test the molecular mechanisms and consequences of ERAAP's role in regulating the peptide repertoires presented by MHC I and MHC II molecules. We will also test the hypothesis that ERAAP polymorphisms influence the peptide presentation by particular MHC molecules that could cause normally tolerated self-peptides to become immunogenic and thus cause autoimmunity. We anticipate the results to provide new insights into the antigen processing pathways and how these pathways could be manipulated to regulate immunogenicity and presently incurable autoimmune disorders.

Public Health Relevance

Autoimmunity results when immune tolerance to self-antigens is disrupted. Understanding how self-antigens are produced by various enzymes will likely reveal potential ways to intervene in autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI060040-16
Application #
9859292
Study Section
Special Emphasis Panel (NSS)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2004-02-15
Project End
2021-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
16
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Pathology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Zhang, Jingtuo; Yang, Soo Jung; Gonzalez, Federico et al. (2018) A peptide-based fluorescent probe images ERAAP activity in cells and in high throughput assays. Chem Commun (Camb) 54:7215-7218
Guan, Jian; Yang, Soo Jung; Gonzalez, Federico et al. (2017) Antigen Processing in the Endoplasmic Reticulum Is Monitored by Semi-Invariant ?? TCRs Specific for a Conserved Peptide-Qa-1b MHC Class Ib Ligand. J Immunol 198:2017-2027
Prasad, Sharanya; Starck, Shelley R; Shastri, Nilabh (2016) Presentation of Cryptic Peptides by MHC Class I Is Enhanced by Inflammatory Stimuli. J Immunol 197:2981-2991
Nagarajan, Niranjana A; de Verteuil, Danielle A; Sriranganadane, Dev et al. (2016) ERAAP Shapes the Peptidome Associated with Classical and Nonclassical MHC Class I Molecules. J Immunol 197:1035-43
Starck, Shelley R; Shastri, Nilabh (2016) Nowhere to hide: unconventional translation yields cryptic peptides for immune surveillance. Immunol Rev 272:8-16
Grover, Harshita Satija; Chu, H Hamlet; Kelly, Felice D et al. (2014) Impact of regulated secretion on antiparasitic CD8 T cell responses. Cell Rep 7:1716-1728
Shastri, Nilabh; Nagarajan, Niranjana; Lind, Kristin C et al. (2014) Monitoring peptide processing for MHC class I molecules in the endoplasmic reticulum. Curr Opin Immunol 26:123-7
Nagarajan, Niranjana A; Shastri, Nilabh (2013) Immune surveillance for ERAAP dysfunction. Mol Immunol 55:120-2
Kanaseki, Takayuki; Lind, Kristin Camfield; Escobar, Hernando et al. (2013) ERAAP and tapasin independently edit the amino and carboxyl termini of MHC class I peptides. J Immunol 191:1547-55
Howland, Shanshan W; Poh, Chek Meng; Gun, Sin Yee et al. (2013) Brain microvessel cross-presentation is a hallmark of experimental cerebral malaria. EMBO Mol Med 5:984-99

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