The mononuclear phagocytes system plays a fundamental role in both innate and adaptive immunity. It includes three broad classes:
- Macrophages, such as alveolar macrophages (AMs), Langerhans cells (LCs), and interstitial macrophages (IMs).
- Circulating monocytes.
- Dendritic cells (DCs), defined by two main types (DC1 and DC2), although DC2 subdivides.
All these MP classes reside in multiple organs. RNA sequencing, single-cell technology, and lineage tracing mouse models have helped define a clear division of labor among the MP classes, demonstrating little to no functional redundancy. This means that specific interactions among these cell types are critical for the optimal immune response against viral, bacterial, fungal, and parasitic infections.
Although most of our understanding of MPs has been investigated in mice, a complete understanding of MP subtypes and their functional role in humans is needed and will provide fundamental advances in immunotherapy, including the ability to:
- Induce immune responses that specifically attack cancer cells.
- Prevent or reverse autoimmune responses that lead to tissue rejection and autoimmune disorders, including lupus, rheumatoid arthritis, allergies, asthma, and more.
- Design more effective vaccines for influenza, malaria, and other diseases by investigating antigen-presenting cells in an unstudied tissue, human skin-draining lymph nodes.
Currently, there are significant gaps in knowledge of how MP subtypes function in human organs, and our lab aims to address them.
Project 1
Identifying and characterizing mononuclear phagocytes cross-species homologies and the key genes conserved across species that are involved in their function, permits both basic and translational advances, including a more accurate picture of which MP subtypes to pursue in a given human application, how to identify these cell types in humans, and which specific genes or proteins to target in treatment development.
Project 2
Yin and Yang of the MPs during inflammation. Like T cells (i.e., T reg and T eff), MPs coordinate the accelerators and breaks of an adaptive immune response. For instance, one of our studies examines on how lymph node, antigen-presenting monocytes and DCs regulate the immune response against a neoantigen conjugated to a TLR3 ligand.
Project 3
The role of B cells and natural antibodies, which are present prior to the encounter with cognate antigens, in cancer immune surveillance.
What led us to initially believe that B cells might play a role in early tumorigenesis was observations from two well-established models. I think of these models as unconventional neoantigen-expressing cell models. The first model is the rejection of male cells in syngeneic female mice. The immune rejection is due to the Y chromosome antigens, which are foreign to female mice. The second model is not H-Y antigen based. With adoptive transfer of MHC-matched 129 female cells into C57BL/6 female mice, 129 cells are rejected. This intact rejection response is due to allelic variations outside of the MHC locus. What these two models have in common is that MHC class I expression is normal, and there is no clustering of cells that results in hypoxic conditions or release of DAMPs, which are required to promote the elimination of precancerous cells as depicted in the elimination phase of cancer immunoediting. Therefore, we asked ourselves: how are these neoantigen-expressing cells (i.e., C57BL/6 male and 129 female cells) identified and eliminated without DAMPs or PAMPs?
This question also came to mind because we know that antigen-bearing DCs require licensing by either DAMPs or PAMPs to present foreign or altered self-antigens in an immunogenic way (Desch et al 2014). The only other mechanism we are aware of that can elicit an immune response to self-antigens without DAMPs or PAMPs are antibodies. Natural antibodies are present prior to the body's encounter with cognate antigen. In a previous study from our lab, we examined the rejection of male cells in female mice using an antibody repertoire deficient mouse and observed that neither male cells nor MHC-matched 129 female cells were rejected in female mice (Atif et al 2019). Upon completion of that study, we realized that what we were observing was an undiscovered mechanism for the early recognition of neoantigen-expressing cells by B cell-derived natural antibodies.
Based on these findings, we are developing studies examining how natural antibodies elicit innate and adaptive immunity in the early stages of tumorigenesis. We address these questions in vivo using three different B cell-deficient mouse strains, transgenic T cells, and natural antibody reconstitution. We continue to find that the intact natural antibody producing-B cell function is necessary for EARLY recognition and elimination of neoantigen-expressing cells. And like myeloid, T, and NK cells, natural antibodies are a significant part of cancer immunosurveillance.