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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
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Craig, Matt
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National Jewish Health
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Gibbings, Sophie L; Jakubzick, Claudia V (2018) A Consistent Method to Identify and Isolate Mononuclear Phagocytes from Human Lung and Lymph Nodes. Methods Mol Biol 1799:381-395
Gibbings, Sophie L; Jakubzick, Claudia V (2018) Isolation and Characterization of Mononuclear Phagocytes in the Mouse Lung and Lymph Nodes. Methods Mol Biol 1809:33-44
Atif, Shaikh M; Gibbings, Sophie L; Jakubzick, Claudia V (2018) Isolation and Identification of Interstitial Macrophages from the Lungs Using Different Digestion Enzymes and Staining Strategies. Methods Mol Biol 1784:69-76
Atif, Shaikh M; Gibbings, Sophie L; Redente, Elizabeth F et al. (2018) Immune Surveillance by Natural IgM Is Required for Early Neoantigen Recognition and Initiation of Adaptive Immunity. Am J Respir Cell Mol Biol 59:580-591
Liu, Huan; Jakubzick, Claudia; Osterburg, Andrew R et al. (2017) Dendritic Cell Trafficking and Function in Rare Lung Diseases. Am J Respir Cell Mol Biol 57:393-402
McCubbrey, Alexandra L; Allison, Kristen C; Lee-Sherick, Alisa B et al. (2017) Promoter Specificity and Efficacy in Conditional and Inducible Transgenic Targeting of Lung Macrophages. Front Immunol 8:1618
Gibbings, Sophie L; Thomas, Stacey M; Atif, Shaikh M et al. (2017) Three Unique Interstitial Macrophages in the Murine Lung at Steady State. Am J Respir Cell Mol Biol 57:66-76
Janssen, William J; Bratton, Donna L; Jakubzick, Claudia V et al. (2016) Myeloid Cell Turnover and Clearance. Microbiol Spectr 4:
Desch, A Nicole; Gibbings, Sophie L; Goyal, Rajni et al. (2016) Flow Cytometric Analysis of Mononuclear Phagocytes in Nondiseased Human Lung and Lung-Draining Lymph Nodes. Am J Respir Crit Care Med 193:614-26
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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