A major obstacle in organ transplantation is the immunological response against donor tissue grafts. Both major (MHC) and minor histocompatibility antigens (mAgs) are known to elicit targeted rejection, and even when a donor's and recipient's MHC antigens are matched, mAgs can elicit graft rejection. In addition, mismatched mAgs are generated in many other settings, such as during tumorigenesis or induction of DNA damage induced by ultraviolet radiation. Thus, understanding the mechanisms by which the immune system recognizes and clears cells expressing mismatches of mAg has broad scientific and translational utility. The rejection of mAg-mismatched cells is complex, involving both adaptive (T cells and B cells) and innate (dendritic cells (DC) and antigen-presenting monocytes) branches of the immune system. To date, it is poorly understood how endogenous antigen-presenting cells recognize, coordinate and induce an immunological response against mAg-mismatched cells, particularly in the absence of pathogen-associated molecular patterns (PAMPs). Preliminary experiments in our laboratory suggest that there is almost no redundancy in the role individual endogenous APC subtypes play to coordinate the rejection of mAg- mismatched cells. Multiple APC subtypes play unique roles in mounting an immune response against mAg- mismatched cells, and blocking any link in the cascade of events should abolish the response against mAg- mismatched cells. If we can better understand the sequential cellular cascade that leads to mAg-mismatched cell rejection, then we can design drugs to target specific cell types and signaling pathways to improve the outcome of transplantation and other adverse diseases. What is novel and most striking about the immunological response we propose to investigate is that the induction of adaptive immunity against mAgs occurs without external stimuli (i.e. PAMPs). Therefore, in Aim 1, we will investigate the role of B cells and the endogenous molecules they secrete to alert the immune system to the presence of mismatches of mAg on cells. We hypothesize that the initial molecule that binds and coats adoptively transferred mAg-mismatched cells are natural IgM antibodies, resulting in the formation of an immune complex.
In Aim 2 we will examine the mechanisms by which a cellular immune complex is acquired by Irf4+ DCs and/or Ly6C+ monocytes. In addition, we will examine how the acquisition of an immune complex activates and licenses Irf4+ DCs and/or Ly6C+ monocytes to present mAg in an immunogenic way to CD4+ T cells. Subsequently, we will investigate how these activated effector mAg-specific CD4+ T cells help license Batf3+ DCs via CD40 to cross-present cell-associated mAgs and prime cytotoxic CD8+ T cells, which is ultimately required to complete the process of mAg-mismatched cell rejection. All in all, the accomplishment of our proposed aims will constitute a significant advance in our in vivo understanding of the cellular and molecular events and mechanisms that regulate the rejection of cells expressing altered minor antigens.

Public Health Relevance

The immune system has evolved to recognize mutations and alterations of minor antigens (mAgs) produced by cancerous tumors, but this adaptive immune response carries costs: The immune system can reject the body's own tissues, as occurs in autoimmune disorders, or other needed tissues, as with organ transplantation. We do not yet understand how endogenous antigen-presenting cells recognize, coordinate and induce immunological responses against mAg-mismatched cells, particularly in the absences of pathogen-associated molecular patterns (PAMPs) that mark foreign agents. If we can uncover the sequential cellular cascade that leads to mAg-mismatched cell rejection, then we can design drugs to prevent tissue rejection, with benefits for transplant surgery, autoimmune disorders, and more.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL115334-08
Application #
9976901
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Craig, Matt
Project Start
2013-01-04
Project End
2021-11-30
Budget Start
2019-08-02
Budget End
2019-11-30
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
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Larson, S R; Atif, S M; Gibbings, S L et al. (2016) Ly6C(+) monocyte efferocytosis and cross-presentation of cell-associated antigens. Cell Death Differ 23:997-1003

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