Immune Cartographers: The Scientists Mapping the Immune Cell Atlas
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Since the discovery of antibodies and phagocytosis heralded the birth of immunology at the end of the 19th century, our understanding of the immune system has increased dramatically.1 However, there are still large gaps in our knowledge of how these cells function, and the role the immune system plays in a range of diseases. Characterization of the multitudes of different human immune cells by phenotype and spatial location is a key step towards fully elucidating immune function and dysfunction in infectious, autoimmune and inflammatory disorders.
For the last several years, this complete mapping of the human immune system has been the goal of the Immune Cell Atlas. This atlas will be a part of the Human Cell Atlas (HCA), a worldwide scientific consortium founded in 2016, which aims to create a cellular reference mapping the position, functions and characteristics of every cell type in the human body.
“The HCA is an open international collaborative consortium whose mission is to create comprehensive reference maps of all human cells as a basis for both understanding human health and diagnosing, monitoring and treating disease,” says
Since its conception, the HCA, co-led by Dr. Regev and Dr. Sarah Teichmann from the Wellcome Sanger Institute, has grown to encompass more than
Capturing the diversity of the immune system
Even as just one Biological Network in the HCA, compiling the Immune Cell Atlas is an enormous task. There are over 30 trillion cells in the human body, and immune cells are almost ubiquitous throughout.2 In fact, the immune portion of the HCA was one of the first areas to be tackled. “Immune cells were some of the earliest cells to be studied with the single-cell techniques that we now rely on heavily, because immune cells in the blood were initially relatively more accessible for these techniques than tissue cells,” says Dr. Regev.
Despite being readily available for sampling, characterizing immune cells can be challenging. Immune cells are extremely adaptive to their environment and will often express a range of different markers or phenotypes, depending on context. “One of the key principles of the Immune Cell Atlas is capturing the diversity of immune cells,” explains Dr. Alexandra-Chloé Villani, director of the single-cell genomics research program for the Center for Immunology and Inflammatory Diseases at Massachusetts General Hospital, a member of the HCA Organizing Committee and network co-ordinator for the HCA Immune BioNetwork, “There’s a lot of donor-to-donor variation, and variation across age, geographic regions and ethnic backgrounds. We also need to consider the plasticity of immune cells, and study them in different contexts, both in healthy donors and different disease states. We’re committed to mapping the whole spectrum of immune cells, across every demographic and perturbation condition.”
Something else to consider for highly variable immune cells, is how to define a distinct cell type, compared to a temporary change in cell state. “Making sure we understand which cell types are there, and their full spectrum of potential states, is part of building a comprehensive atlas,” explains Dr. Regev. “These distinctions between types and states are not simple. Immune cells especially can be more malleable, or span a spectrum of states/types. Analyzing gene programs – sets of co-varying and often co-functional genes – can help us understand both.”
In order to help decipher the phenotypes of different immune cells and their functions in various disease states, Dr. Regev’s research group pioneered computational methods in single-cell genomics. “In 2018, our lab contributed the first dataset to the Immune Cell Atlas, consisting of 1 million single-cell profiles of immune cells” Dr. Regev says.3 “Since then, we have continued to probe the identity and function of immune cells throughout the body, in different disease contexts including many kinds of cancer, inflammatory and immune diseases and COVID.”4,5,6,7
A window into human health
Once complete, the Immune Cell Atlas will include immune cells from every aspect of the body, including primary and secondary lymphoid organs, and non-lymphoid tissues such as the skin and lungs. However, blood has so far been profiled most extensively by single-cell sequencing. “Blood, in some senses, is a window into human health,” Dr. Villani explains. “It’s easily sampled, and extremely useful in diagnostics. Blood studies are often focused on a single disease and individually small in scale, but in combination may have potential to produce new biological insights. As such, we need to start integrating data across studies to convert that into clinical utility.” Dr. Villani’s research group is currently working on integrating several data sets cumulating to 14 million blood cells gathered from both healthy donors and 27 distinct infectious and autoimmune disease states. “The goal here isn’t to create a detailed map of 27 distinct disease states,” clarifies Villani. “But to capture all possible immune cell identities by studying them across a range of different contexts and looking for common and distinct biological principles.” Once fully collated, these data will be an important resource for the Immune Cell Atlas and the wider field of immunology, to help elucidate the spectrum of health and disease.
Dr. Villani and Regev’s earlier collaborative work using single-cell RNA sequencing (RNA-seq) to identify immune cells in blood samples helped fuel the formation of the HCA. The investigation identified a novel subset of dendritic cells (DCs) with T cell activating properties, and presented evidence supporting a taxonomy revision for wider DC subtypes.8 “We showed that it’s possible to predict the existence of a novel cell type through single-cell multiomics profiling, identify markers and then functionally characterize the cells to show they were truly distinct,” says Dr. Villani. This proof of principle study showed that new cell subsets could be identified through single-cell genomics analysis and further characterized using orthogonal approaches, which helped to build the foundational strategies now used across the HCA consortium.
Incorporating new knowledge into the old
For centuries, scientists have endeavored to catalog, classify and annotate cells of the human body, but only recently has this been possible at such a specific, single-cell, molecular resolution and on such a huge scale. The development of highly accurate single-cell genomics techniques has enabled the simultaneous genome-wide quantification of mRNA in hundreds of thousands of cells. Integrating these methods with multiomics measurements (including transcriptomics, proteomics and epigenomics) helps to build a comprehensive picture of an individual cell’s properties, identity and relationships to other cells within the human body.9
However, using these novel methods isn’t without its challenges. “To really build a sophisticated view of a cell, you need to layer lots of different identities together, then try to sum them up and understand how they relate to the historical definition of the cells,” says Dr. Villani. “One of the challenges is that subsets of cells reported previously have been defined using limited sets of parameters, which makes it difficult to relate them to our new discoveries.” If the Immune Cell Atlas is to become a useful resource, accurately defining the identity of these cells using annotation terminology agreed upon within the immunology community is essential.
To ensure this, the HCA consortium is developing a centralized platform for researchers to annotate cells, aggregating the molecular signatures used to define cells and the nomenclature used by individual researchers. This endeavor, known as the Cell Annotation Platform (CAP), is led by Dr. Villani and will be one of the key components of the HCA project. “The process of giving a cell type an identity is a cornerstone of biological research,” says Dr. Villani. “We’ve created an open-source centralized repository of persistent cell types and associated data sets. It allows a wide range of users to browse annotations of individual studies and give feedback on what we think is a unique cell type. We’re hoping it will bring classically trained immunologists together with experts in single-cell genomics to start deriving a common lexicon and consensus on cell identities.” The meta data collected in the CAP will also eventually empower machine learning approaches to provide automated cell annotation predicted for researchers to review for future datasets.
Mapping the immune environment of tumors
One important context for the immune system is malignancy and cancer. The immune system recognizes abnormal proteins on the surface of cancer cells, and targets them for destruction, therefore playing a key role in the control and clearance of tumors. In response, tumors engage in immunosuppressive and immune-evasive mechanisms. The tumor microenvironment often has a unique immune cell signature, which, if fully elucidated, could aid in the design of improved therapies or clinical outcome predictions.
Several projects in the HCA focus on exploring the single-cell immune profiles of different cancers to reveal clinically relevant subpopulations.10,11,12 For example, one Immune Cell Atlas project examining the immune environment in clear cell renal carcinomas used single-cell RNA-seq and spatial techniques to discover a subpopulation of tumor-specific macrophages. Abundance of these macrophages were observed to increase in patients who suffered recurrence. Thus, the research identified these cells as both a potential prognostic biomarker and a potential target of therapy, and demonstrated the potential impacts of the HCA.13
The collaborative benefits of the HCA as a whole to subsequent research is already being seen, with Dr. Villani’s research as a prime example. One of her research projects examines immune-related adverse events (irAEs) to immune checkpoint inhibitor (ICI) treatment, a form of cancer immunotherapy. “We’ve been collecting clinical samples across organ systems affected by irAEs and are using single-cell multiomics strategies to analyze paired tissue and blood specimens to develop a detailed understanding of the molecular and cellular pathways involved in driving and sustaining irAEs ,” Dr. Villani explains. “And because we can work in the greater sphere of the HCA and the Immune Cell Atlas, we can get a better understanding of the biological context across organs through which these irAEs can develop.”14,15 The researchers were able to use data from another BioNetwork - the Heart Biological Network– as a reference, to help identify subpopulations of immune and non-immune cells involved in driving and sustaining ICI-myocarditis pathogenesis.
Informing future therapies
Immune cells are found throughout the body and are now thought to play a role in almost all disease processes, whether communicable or not. Full characterization of the immune system and how it functions in different disease states would pave the way for new, more efficient treatments. Understanding how the immune system reacts in response to pathogens would allow the development of better targeted vaccines, for example. A comprehensive tumor immune atlas would enable the creation of safer, more efficient immunotherapies for cancer.
Diagnostics could also be improved by the completion of the Immune Cell Atlas. “Right now, one of the most common diagnostic tests used in the clinic is the complete blood count (CBC), which tallies the numbers of certain kinds of blood and immune cells in a patient’s blood sample,” says Dr. Regev. “But these categories are actually very broad, so having a fuller picture of the kinds and states of immune cells in the blood and their roles would allow for the development of a much more specific diagnostic test - a “CBC 2.0.””
Ultimately, the Immune Cell Atlas will serve as a comprehensive, collaborative resource to benefit researchers all around the world in better understanding health and disease. However, it’s an ongoing endeavor with far more data needed before it can be considered complete.
“It’s not a select club, it’s a grassroots initiative. Everybody is welcome to join us!” exclaims Dr. Villani.
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