Immunologists, understandably, have historically focused on the most recognizable effector cells of our innate and adaptive immune responses. Macrophages, neutrophils, and lymphocytes, among others, have been “the stars” of our show. But like any major production, success of these stars absolutely depends on their supporting cast, who nurture and direct their development and performances. For the immune system, we now recognize that critical members of the supporting cast fall under the broad category of stromal cells. We have long known that stroma provides physical support for hematopoietic cells; however, it is increasingly appreciated that stromal cells have a profound effect on the development, magnitude, and character of immune responses. As a few examples, stromal cells at barrier surfaces can initiate responses to microbes, stromal cell subsets act as unique and indispensable APCs that regulate T cell differentiation, and each tissue environment shapes distinct differentiation trajectories of infiltrating myeloid cells.
Our understanding of stromal cells in immunity has lagged primarily for technical reasons. Many types of hematopoietic cells rapidly migrate and are loosely attached to the tissue environment, facilitating their isolation for analysis and adoptive transfer. By contrast, stromal cells are often lost in the processing of tissues. Studies of hematopoietic cells also benefit from a wide array of well-characterized, unique markers for identification of developmental and functional subsets. Importantly, some of these markers can even be leveraged therapeutically, as in the case of CD19, which has been an extraordinarily effective target for lymphoma/leukemia immunotherapy because of its nearly exclusive expression on B cells. By comparison, stromal subsets often are defined by combinations of markers that are not exclusive to one cell type but instead are expressed at sometimes subtly distinct levels.
Recent technical advances, including single-cell or single-nucleus sequencing and imaging mass cytometry, have propelled many new insights into stromal cell biology. Coupled with the growing set of approaches to manipulate gene expression in stromal cells, the field is ripe for a new series of breakthroughs that will impact our understanding of the immune system in health and disease. Accordingly, we are devoting the 2021 Topical Review Issue to this breaking field, which highlights our current understanding of how mesenchymal, epithelial, and endothelial cells shape immunity, as well as the most important challenges and questions that we face. We also welcome The Journal of Immunology’s first guest editor, Susan Schwab, Ph.D., associate professor at New York University Grossman School of Medicine, whose expertise has guided and enhanced this stellar collection, entitled “Stromal Immunology: Frameworks for Development and Response.”
The collection appropriately begins in the thymus, where T cells are born, with Brown and Rudensky’s Pillars of Immunology commentary (1) on “Projection of an Immunological Self Shadow within the Thymus by the Aire Protein.” The authors provide a beautiful perspective on a foundational paper from the Mathis and Benoist laboratory that identified AIRE as essential for a subset of thymic epithelial cells to present peripheral tissue Ags to developing T cells, thereby preventing pathogenic, self-reactive T cells from leaving the thymus. Han and Zúñiga-Pflücker (2) then present a broader review of thymic stromal cells, which provide indispensable cues to support thymocyte survival and differentiation into mature T cells. Ultimately, an understanding of how the thymic stroma “rear” functional T lymphocytes from immature progenitors may lead to more advanced techniques for culturing T cell therapeutics.
After mature lymphocytes exit the thymus or bone marrow into the blood, they circulate among the secondary lymphoid organs. For this stop, Pikor et al. (3) provide a review of lymph node stromal cells, which choreograph a series of complex dances that capture lymphoid and myeloid cells from circulation, drive rare Ag-specific lymphocytes to find their match, direct activated lymphocytes to the correct microenvironments for differentiation, and ultimately send a small army of Ag-specific lymphocytes back into circulation. The authors explain that stromal cells rapidly adapt their functions to different inflammatory contexts. Although blood brings lymphocytes into lymph nodes, lymph carries free Ag and APCs to their meeting place in these peripheral lymphoid organs. Steele and Lund (4) review the cross-talk between hematopoietic cells and lymphatic endothelial cells, revealing how this dialog regulates the flow of fluid and cells out of tissues, profoundly impacting the course of infections.
During persistent inflammation, nonlymphoid stroma can assume characteristics of lymph node stromal cells, nucleating the formation of organized tertiary lymphoid organs. Gago da Graça et al. (5) review our understanding of these structures, which have been implicated in the progression of autoimmune disease and cancer, with important therapeutic implications. As the authors point out, it will be fascinating to understand how the nature of tertiary lymphoid structures reflects the identity of the host tissue and/or a specific type of disease.
From there, we move to the next stop for lymphocytes, in which they traffic to inflamed tissues. First, Ramaglia et al. (6) review stroma in brain-adjacent regions, the leptomeninges, choroid plexus, and Virchow–Robin spaces, each of which has a unique, specialized anatomy. This is a critical area for discovery, because even the basic anatomy of how cells and soluble molecules drain from the CNS remains relatively unknown. Royer and Cook (7) then focus on the role of lung epithelial cells in asthma, discussing how diverse epithelial subtypes, some of which have been described only recently, act in concert to detect and eliminate microbes, using a multiplicity of channels to communicate their findings to hematopoietic cells, and how these processes go awry in allergic disease. Sim et al. (8) then review the cross-talk between skin stromal and immune cells in the context of lupus, an autoimmune disease characterized by inflammatory skin lesions. The authors highlight circuits that link hematopoietic and stromal cells to amplify tissue damage.
Finally, we examine how many of the essential physiologic roles of stromal cells become pathological in the context of cancer. Baker et al. (9) review the myriad ways that cancer-associated fibroblasts limit immune responses to solid tumors. Novel cancer immunotherapy strategies simultaneously bolster the T cell response while inhibiting cancer-associated fibroblast activity, targeting both hematopoietic and stromal cells. These promising approaches build on many of the studies reviewed in this issue, describing how stromal cells regulate normal immune cell development, activation, and effector function.
This review collection also highlights a range of key questions for the future, including: 1) Do distinct stromal microenvironments in the lymph node support differentiation of distinct types of T cells? 2) How do lymphatics regulate lymphocyte trafficking from tissues to the draining lymph nodes, and how does this differ among tissues and diseases? 3) How does the nature of tertiary lymphoid structures reflect the underlying tissue or disease? 4) Do stromal cells retain epigenetic “memory” of past inflammation, and can they be reprogrammed? 5) How can we best target T lymphocytes and stromal cells in concert to improve cancer immunotherapy? New tools, including creative combinatorial strategies to drive Cre recombinase expression, will be invaluable to shed light on these areas. The advances reviewed in this issue provide a strong “stroma” to nurture and shape these future discoveries.