Minor histocompatibility (H) antigens (Ags) play a detrimental role in the immunopathogenesis of graft-vs-host disease (GvHD) even in recipients of HLA identical bone marrow transplants. Herein, recipient minor H Ags are acquired by donor Ag-presenting cells (APCs) and processed and presented either by MHC class I molecules in a well studied process termed cross-presentation or by class II molecules in a less well understood process called indirect presentation. In a solid organ transplant setting, indirect presentation entails the acquisition, processing and presentation of donor alloantigens by the recipient's APCs. In the case of tumour and microbial Ags, a class II+ APC-likened to a recipient cell-acquires the Ag residing in a class II-negative cell-likened to a donor cell-and processes and presents it to cognate CD4+ (T ) cells. Our mechanistic studies into indirect H presentation revealed that the male pHY and Listeria monocytogenes-derived pLLO Ags upon acquisition by the recipient APCs gained access to the cytosol. Herein, the indirect presentation of pHY was immunoproteasome-dependent yet TAP (cytosol to ER peptide transporter)- and ERAAP (ER-associated amino-peptidase)-independent. Surprisingly, both TAP and ERAAP either diverted or destroyed pHY and pLLO thereby reducing their presentation to TH cells. These finding led to two critical questions: (a) does the class I Ag processing (CAP) machinery globally impact class II-restricted Ag presentation;and (b) how do cytosolic Ags gain access to the endo/lysosomes for indirect presentation? In trying to understand how the cytosolic pHY returned to the endo/lysosomes for presentation, we ruled out the role for macro-autophagy as indirect presentation of HY proceeded in mice in which dendritic cells were conditionally deficient for Atg5. Instead, we found that the homodimeric TAP-like (TAP-L)-an orphan endo/lysosomal peptide transporter distinct from ER- resident TAP1/TAP2-was needed for indirect pHY presentation. Predicated on our functional studies, herein, we seek to gain biochemical insights into indirect presentation mechanism(s). Hence, we will test the central hypothesis that the class I Ag processing machinery regulates the pool of certain cytosolic Ags available for class II-restricted indirect presentation. Such Ags are processed in the cytosol and transported to the endo/ lysosomes in a TAP-L-dependent mechanism. To test this hypothesis, we will (a) determine whether the CAP machinery globally impacts H2Ab-restricted processing and presentation of self- or microbe-derived cytosolic Ags;(b) determine how cytosolic Ags enter the endo/lysosomes for indirect presentation;and (c) determine whether the CAP machinery impacts cytosolic Ag specific CD4+ T cell repertoire. Successful completion of this work will yield new biochemical insight(s) into indirect Ag presentation by class II molecules. A mechanistic understanding of class II-restricted indirect Ag presentation is critical not only for developing ways to circumvent/treat GvHD but also for vaccine design as this process is operative in the presentation of cytosolic Ags (viral, bacterial, parasitic) to TH cells and, hence, for vaccine design against tumours and pathogens. !

Public Health Relevance

Bone marrow transplantation has emerged as a therapeutic modality for various end-stage blood cell diseases such as anemias, lymphomas and leukemias. Even though matching major histocompatibility complex antigens has improved transplant outcome, minor histocompatibility antigen mismatches are known to cause, oft-times fatal, graft-vs-host disease. The goal of this research is to gain a mechanistic understanding of how minor histocompatibility antigens are processed and presented to T cells so as to develop ways to circumvent or treat fatal, graft-vs- host disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL121139-01
Application #
8614968
Study Section
Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
Program Officer
Welniak, Lisbeth A
Project Start
2014-05-15
Project End
2018-04-30
Budget Start
2014-05-15
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Nashville
State
TN
Country
United States
Zip Code
37212
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