Peptides derived from foreign and self antigens are presented in the context of MHC class II molecules for recognition by CD4+ T cells. Class II molecules transit the endosomal network of cells, acquiring peptides from exogenous antigens as well as endogenous cell surface and endosomal proteins. Surprisingly, epitopes from cytoplasmic antigens also are presented by class II molecules. The overall goal of this proposal is to understand the mechanisms regulating class II cytoplasmic Ag presentation, and to identify new means to modulate immunity to self and tumor Ags. With subversion of class I presentation by tumors and viruses, exploiting novel pathways for cytoplasmic Ag presentation remains important. Targeting specific cytoplasmic Ags for class II presentation offers a unique approach to promote immune recognition and overcome such immune evasion. The current proposal focuses on a selective pathway, chaperone mediated autophagy (CMA) which facilitates class II cytoplasmic antigen presentation. We propose that cytoplasmic antigens are selectively targeted by cytosolic chaperones for proteolysis during CMA. The resulting peptides may then be chaperoned to a membrane transporter, LAMP-2A for translocation into the endosomal network for class II presentation. Studies are proposed to define the importance of chaperones, HSC70 and HSP90 in guiding cytoplasmic antigens for processing and translocation into organelles for class II presentation. Multiple isoforms of the LAMP-2 gene are expressed in B cells and melanomas, potentially regulating class II cytoplasmic antigen presentation by autophagy. Studies are proposed to elucidate the role of individual LAMP- 2 isoforms in class II presentation pathways. This project will offer critical insights into the molecular events and essential co-factors for CMA which faciliate class II access to cytoplasmic antigens for immune recognition. Notably, autophagy pathways are often up-regulated in tumor cells to promote tumor growth and survivial. Such changes in cellular autophagy pathways may enhance tumor antigen recognition. Studies in this project will examine the importance of distinct autophagy pathways in cytoplasmic antigen presentation by melanomas. This work also has relevance to our understanding of autoimmunity to self antigens and tolerance induction. Exploiting the selectivity of the CMA pathway may also offer opportunities for novel approaches to vaccine development.

Public Health Relevance

This work has relevance to our general understanding of how the immune system distinguishes self and foreign molecules. The project has implications for cancer as autophagy is often up-regulated in tumors, and this could be exploited to promote immune recognition of tumor cells. These studies may also be important in understanding autoimmunty, and lead to new approaches for vaccine development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI079065-03
Application #
8260287
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$343,035
Indirect Cost
$120,285
Name
Indiana University-Purdue University at Indianapolis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Troxell, Bryan; Zhang, Jun-Jie; Bourret, Travis J et al. (2014) Pyruvate protects pathogenic spirochetes from H2O2 killing. PLoS One 9:e84625
Walline, Crystal C; Deffit, Sarah N; Wang, Nan et al. (2014) Virus-encoded ectopic CD74 enhances poxvirus vaccine efficacy. Immunology 141:531-9
Watkins, Renecia A; Evans-Molina, Carmella; Blum, Janice S et al. (2014) Established and emerging biomarkers for the prediction of type 1 diabetes: a systematic review. Transl Res 164:110-21
Chang, Hua-Chen; Lewis, David; Tung, Chun-Yu et al. (2014) Soypeptide lunasin in cytokine immunotherapy for lymphoma. Cancer Immunol Immunother 63:283-95
Blum, Janice S; Wearsch, Pamela A; Cresswell, Peter (2013) Pathways of antigen processing. Annu Rev Immunol 31:443-73
Pham, Duy; Walline, Crystal C; Hollister, Kristin et al. (2013) The transcription factor Twist1 limits T helper 17 and T follicular helper cell development by repressing the gene encoding the interleukin-6 receptor * chain. J Biol Chem 288:27423-33
Walline, Crystal C; Sehra, Sarita; Fisher, Amanda J et al. (2013) Allergic airway disease in mice alters T and B cell responses during an acute respiratory poxvirus infection. PLoS One 8:e62222
Wu, Lingyan; Yan, Cong; Czader, Magdalena et al. (2012) Inhibition of PPARýý in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis. Blood 119:115-26