Mapping the Body’s Defense System: The Immune Cell Atlas

The human immune system comprises many cell types, ranging from microbe-engulfing macrophages to antibody-producing B cells. Characterizing these cells by their location within the body, and their phenotype during both healthy and diseased states, is a rapidly growing field.

Researchers are in the process of mapping the human immune system in its entirety across time and space to create the Immune Cell Atlas. This atlas will be a portion of the Human Cell Atlas –a complete map of every cell type in the human body, made possible through global research collaborations.

“The international Human Cell Atlas consortium is mapping every cell type in the human body, as a basis for both understanding human health and diagnosing, monitoring and treating disease. To assist with this are 18 biological networks that focus on different tissues, organs or systems within the body,” says Dr. Sarah Teichmann, head of cellular genetics at the Wellcome Sanger Institute and co-chair of the Human Cell Atlas organizing committee.

The combined efforts of the Immune BioNetwork, one of the 18 biological networks contributing to the Human Cell Atlas, and the Immunological Genome Project, a group of computational and immunology labs that share their data with the public, are mapping the immune system one immune cell at a time to bring the Immune Cell Atlas to life.

“The Immune BioNetwork, in partnership with the Immunological Genome Project, is analyzing gene expression in immune cells at single-cell detail,” says Dr. Teichmann. 

One map to rule them all

Professor Muzlifah Haniffa, professor of dermatology and immunology at Newcastle University and associate faculty at the Wellcome Sanger Institute, says, “The goal of the Immune Cell Atlas is to comprehensively map the composition of the human immune system, its cells and their characteristics across (the human) lifespan during health as a reference to understand what goes wrong in disease.”

Profiling immune cell types in human lymphoid and non-lymphoid tissues in healthy individuals as a baseline and during disease will offer researchers a complete map of the immune system. The completed map will act as a guide to improve diagnostics and therapeutics for a myriad of diseases and disorders.

“The immune system includes primary lymphoid tissue, such as the thymus and bone marrow, secondary lymphoid tissue, like the lymph nodes and spleen, and immunocytes in non-lymphoid tissues such as lung, skin and gut,” says Dr. Teichmann. “The Immune BioNetwork will survey immune cells across the body in unprecedented breadth and detail and is likely to resolve hundreds of specific immune cell types.”

Researchers that publish findings relating to the Immune Cell Atlas are sharing the data globally to provide transparency and accessibility.

Dr. Teichmann explains, “The research involves global collaboration to analyze the immune response to many infectious and inflammatory diseases around the world.  The openly available data will radically transform our knowledge of immune function and our understanding of what goes wrong in infectious diseases, autoimmune or inflammatory disorders. This knowledge could also reveal the role of immunocytes in other diseases such as cancer or type 2 diabetes.”

Expansion of Specific Lymphocyte Populations

The success of CAR T-cell therapy requires efficient expansion of specific subpopulations of patient-derived immune cells. Download this app note to discover the benefits of using a xeno- and serum-free medium for cell expansion.

View App Note

Sponsored Content

Mapping immune cells from early life to adulthood

One key goal of the Immune Cell Atlas is to uncover how the immune system develops during pregnancy.

Professor Haniffa explains, “A key finding from a recent study revealed, composition and gene expression changes that occur to immune cells across prenatal organs over time, which enabled us to construct the dynamic processes of the developing immune system.¹”

Researchers have also recently discovered how the developing immune system is supported by multiple organs, some of which were a surprise.

“Our comprehensive atlas of the developing human immune system across organs revealed that blood and immune cells are created in diverse tissues in human development including skin and gut, not just in the organs previously known to manufacture immune cells,¹” says Dr. Teichmann.

Beyond understanding the immune system’s development, the Immune Cell Atlas is also providing researchers with the ability to confirm that cell types present in mouse models are also present in humans.

“The study provided identification of innate B1 cells that can secrete antibodies spontaneously.¹ These cells were previously described in the mouse but their existence in humans had been elusive,” describes Professor Haniffa.

Studies related to the Immune Cell Atlas are also uncovering new subsets of immune cells in human tissues and showing how these subsets are distributed within tissues throughout the body.

“We sequenced RNA from 330,000 single immune cells from across the adult body to understand the function of immune cells in different tissues.² Our team developed a database and algorithm called “CellTypist,” and through this we were able to identify about 100 distinct types of immune cells,” says Dr. Teichmann. “We not only discovered specific subsets of T cells and effector memory killer T cells, but also revealed that they had different tissue distributions. This could have great implications in managing infections.”

Furthermore, understanding how this multitude of immune cells develop can offer insights that feed into the development of more robust therapeutics. “We showed that innate/unconventional T cells are selected using a different process to conventional T cells in the thymus.¹ These innate cells undergo thymocyte-based selection, and we proved this using a laboratory T-cell culture system,” explains Professor Haniffa. “These findings help reveal the necessary ingredients and conditions for human T-cell engineering that can be used for therapy.”

Discover the Freshness of Frozen PBMCs

Human peripheral blood mononuclear cells (PBMCs) are used to determine whether a drug will elicit a T-cell response. Download this app note to discover the experimental methods used to determine the impact of cryopreservation on PBMCs

View App Note

Sponsored Content

Untangling autoimmunity

The immune system is supposed to protect the human body from invading pathogens. But, at times, this biological defense system goes rogue and attacks the tissue and organs of the human body, resulting in autoimmune disorders. Some well-known examples include diabetes mellitus type I, lupus and vitiligo.

Understanding what a healthy immune system looks like is key to improving therapeutics for these types of disorders. Researchers are still unraveling the mechanisms behind many autoimmune states and the Immune Cell Atlas will serve as a reference to advance our comprehension of these disorders.

“By revealing the immune cell types and pathways involved in development and homeostasis, this guidebook of healthy immune cells can provide a framework against which to benchmark changes in disease such as autoimmune disease,” Dr. Teichmann explains.

Furthermore, the Immune Cell Atlas could potentially serve as a tool to help prevent autoimmunity altogether.

“By understanding the composition of the immune system and how it works as a whole in health, it will enable us to understand what goes wrong in autoimmune disorders that results in self-damage. In addition, by knowing more about the unique features of rogue cells mediating autoimmunity, we can find ways to halt or reverse their function. Ultimately, we will have the knowledge to not just delay or reverse autoimmunity, but also to prevent autoimmunity,” says Professor Haniffa. 

PD-1/PD-L1 Combination Therapy in Cancer Treatment

Programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade therapy is a new class of anticancer immunotherapy that utilizes the body’s immune system to resist cancer and causes cancer cell death by blocking the PD-1/PD-L1 signaling pathway. Download this whitepaper to learn more about blockade therapy resistance and combination therapy with CTLA-4 blockers.

View Whitepaper

Sponsored Content

COVID-19: Mapping a viral pandemic

COVID-19, caused by the virus SARS-CoV-2, has been at the forefront of the research world for the past two and a half years. Researchers have been in a race against time to understand how this virus affects the human body and how the immune system responds to it.

“Human Cell Atlas researchers came together very quickly at the start of the pandemic to help understand COVID-19,” says Dr. Teichmann. We discovered that ciliated and goblet-cells in the nose³ are likely initial infection points for SARS-CoV-2, and also revealed salivary glands as sites of infection.⁴ These were in healthy, non-infected individuals.”

SARS-CoV-2 infection can result both in acute infection and in serious, lingering sequalae known as long COVID. These sequalae can range from blood clots to cognitive fatigue.

“We have also been studying immune responses during the acute phase of COVID-19 infection in adults and children,” Dr. Teichmann elaborates. “For example, by comparing patient nasal and blood samples to healthy reference states, we have been able to show that a rapid immune response in children protects them from COVID-19,⁵ and that asymptomatically infected people have different immune responses compared to those with severe COVID-19.⁶ This approach could also be used to help uncover the biology behind long COVID by comparing the guidebook Immune Cell Atlas data from healthy people with cells from people with long COVID.”

Researchers are still unraveling the mechanisms behind long COVID, thus, the Immune Cell Atlas will be a valuable tool for this field of research.

Analysis of Non-Blood Body Fluids

The best fluids for mining disease biomarkers are closest to the site of pathology. Watch this webinar to learn about the assessment of non-blood body fluid proteomes, testing urine, cerebrospinal fluid and stool samples, and emerging approaches that could shed insights on disease pathways and mechanisms.

Watch Webinar

Sponsored Content

Future impact on medicine and research: Potential therapies

Crosstalk between the immune system and other biological processes within the body, such as the cell cycle or tumor microenvironments, make it a key target to elucidate. Furthermore, understanding the immune system and the cells that comprise it are essential to the development of efficacious therapeutics.

“The immune system affects virtually every organ in the human body and forms a dynamic functional network. It has the capacity to learn and form immunological memory to microbial challenge. It is now clear that almost all disease processes involve alterations to or response from immune cells, such as cancer and neurodegeneration, that have traditionally not been associated with immune cells,” explains Professor Haniffa. “In these diseases, for example cancer, immune cells can be harnessed for therapeutic purposes. Immunotherapy with checkpoint inhibitors is a great example of leveraging immune cell functions against cancer.”

The Immune Cell Atlas also has the potential to impact research focusing on regenerative medicine.

“Understanding how the immune system develops could act as framework for developing therapies to fight immune-related diseases and serve as a guidebook for in vitro cell engineering and regenerative medicine research in the future,” says Dr. Teichmann.

The Immune Cell Atlas will also pave the way for more efficient vaccines and cancer therapeutics. Dr. Teichmann further explains, “A detailed understanding of tissue-resident immune cells will help towards vaccine design and inform the site of delivery. In another example, knowing the code of which molecules direct T cells to specific tissues and maintain them in that location is important for engineering and targeting T cells e.g., for cancer therapies.”

Ultimately, the Immune Cell Atlas will act as a comprehensive guide for researchers to understand disease states, allowing them to create new and more efficacious therapeutics, ranging from autoimmune disorders to cancer to vaccines.

“All areas of medicine and research will be impacted,” declares Professor Haniffa.

References

1.      Suo C, Dann E, Goh I, et al. Mapping the developing human immune system across organs. Science. 2022;376(6597):eabo0510. doi: 10.1126/science.abo0510

2.      Domínguez Conde C, Xu C, Jarvis LB, et al. Cross-tissue immune cell analysis reveals tissue-specific features in humans. Science. 2022;376(6594):eabl5197. doi: 10.1126/science.abl5197

3.      Sungnak W, Huang N, Bécavin C, et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020;26(5):681-687. doi: 10.1038/s41591-020-0868-6

4.      Huang N, Pérez P, Kato T, et al. SARS-CoV-2 infection of the oral cavity and saliva. Nat Med. 2021;27(5):892-903. doi: 10.1038/s41591-021-01296-8

5.      Stephenson E, Reynolds G, Botting RA, et al. Single-cell multi-omics analysis of the immune response in COVID-19. Nat Med. 2021;27(5):904-916. doi: 10.1038/s41591-021-01329-2

6.      Yoshida M, Worlock KB, Huang N, et al. Local and systemic responses to SARS-CoV-2 infection in children and adults. Nature. 2022;602(7896):321-327. doi: 10.1038/s41586-021-04345-x