A First Step Toward a Cross-tissue Atlas of Immune Cells in Humans : Transplantation

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A First Step Toward a Cross-tissue Atlas of Immune Cells in Humans

Cippà, Pietro E. MD, PhD1; Mueller, Thomas F. MD2

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Transplantation 107(1):p 8-9, January 2023. | DOI: 10.1097/TP.0000000000004349
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The mutual interaction between immune cells and peripheral tissues regulates many biological processes that include immune responses to local infections in addition to the maintenance of immunological tolerance or tissue repair.1-3 Until recently, most studies on human immunity have emphasized on the blood compartment, thereby missing the impact of the local microenvironment on differentiation, function, and fate of the directly involved immune cells. Increasing evidence supports a critical role of the tissue-based control of the immune system in organ transplantation and particularly in the still incompletely understood mechanisms of late forms of allograft rejection.4,5 Recently, the application of single-cell RNA sequencing confirmed significant differences in immune cells obtained both allografts and peripheral blood, stressing the need to specifically investigate common and tissue-specific features of local immune cells for a better understanding of the fundamental mechanisms of rejection and tolerance after solid organ transplantation.6

In a recently published manuscript in Science, Domínguez Conde et al7 introduced a new immune cell reference atlas. The authors characterized by cross-tissue single cell RNA sequencing (including VDJ sequencing for B- and T- cell receptors) ~300,000 immune cells isolated from bone marrow, thymus, lung-draining lymph nodes, mesenteric lymph nodes, spleen, lungs, liver, omentum, skeletal muscles, duodenum, jejunum, cecum, transverse colon, and sigmoid colon from 12 deceased organ donors. A novel computational tool (CellTypist) was developed to automatically annotate immune cells across organs. The heterogeneity of the immune cells was remarkable: the authors found 101 immune cell populations, reflected in their unique morphological, functional, and transcriptional profiles with a restricted tissue distribution in some lineages (macrophages, eg, displayed pronounced tissue-specific adaptations) and convergent features in others.

In the B-cell compartment, the authors identified 9 cell populations. The authors characterized phenotype and tissue distribution of age-associated B cells, a subset of CD11c+T-bet+ nonclassical B cells, previously reported in autoimmunity and aging.8 Immunoglobulin class switch in memory B cells, plasmablasts, and plasma cells showed a bias toward IgA1 in mesenteric lymph nodes and toward IgA2 in the ileum, consistent with previous findings. In bone marrow, liver, and spleen, IgG2 was the dominant class in plasma cells. The distribution of expanded B-cell clones across tissues was consistent with the accumulation of tissue-restricted clones including plasma cells, whereas memory B-cell clones were broadly distributed across tissues.

The large compartment including innate lymphocytes and T cells consisted of 18 clusters, ranging from naive CD4 and CD8 T cells to subsets of effector, follicular, and regulatory T cells, to natural killer cells and mucosal-associated invariant T cells. The T-cell receptor repertoire of mucosal-associated invariant T cells displayed significant differences among organs, suggesting the interaction with different antigens and metabolomes in the local microenvironment. The T-cell receptor repertoire analysis revealed that individual clonotypes were restricted to single donors but differently distributed within the same organism. In fact, the most expanded clonotypes were distributed across >5 organs, consistent with the systemic nature of immune memory. Notably, some clonotypes were shared among regulatory and effector CD4+ T cells and among different CD8+ T-cell subtypes, probably reflecting divergent differentiation of lymphocytes generated from the same precursor or plasticity of peripheral T cells.

This extensive work, embedded in the Human Cell Atlas project, highlights the fascinating landscape of tissue-specific and unspecific immunity. Some findings are particularly relevant in addressing key dilemmas in transplantation immunology emphasizing on the importance of organ-specific immunogenicity, the individualization of immunosuppression, the link between organ quality, injury, and immunity, the unpredictability of treatment responses to rejection or the phenomenon of accommodation. Clearly, understanding tissue-based regulation of the local immune response might define novel options for immune modulation and particularly for the development of targeted cell therapies to prevent organ rejection, induce tolerance, and reduce off-target side-effects. To get closer to these goals, it will be necessary to present data on immune cells in organs of critical clinical relevance in transplantation, such as kidney and heart in future studies. The precise characterization of the B-cell compartment, including clonal distribution of memory B cells and plasma cells, might be relevant for novel strategies to facilitate transplantation in sensitized recipients and to treat late forms of allograft rejection, in consideration of previous studies linking tissue injury and late B-cell activity after kidney injury and repair.4 Indirect evidence for clinical T-cell plasticity in peripheral tissues may support the development of targeted immunotherapy for the expansion of donor-specific regulatory T cells in vivo.9

The presented data also highlight limitations of the currently available data and technologies in this area of research. For myeloid cells, the authors found a specific population of TNIP3 expressing alveolar macrophages, primarily detected in 1 donor after a polytrauma that included lung contusion. This finding highlights that this reference atlas, mainly generated by analyzing “normal” organs, might only reflect a limited part of the complexity generated by recruitment, expansion, and local differentiation of immune cell types or states in pathological conditions. The characterization of only 12 individuals might also be insufficient to define a reliable reference atlas clinically. Moreover, other critical variables such as age, sex, and therapy were not specifically addressed. New technologies enabling the combined detection of transcriptomics, chromatin profiling, and cell surface markers at the single-cell level might be instrumental in the future to validate and correctly interpret further levels of heterogeneity.10

In conclusion, this cross-tissue analysis provides a new reference atlas of the immune system, highlighting the enchanting complexity of human biology enriching future research in transplantation immunology. Despite the large amount of data supporting the presented analyses, this is only the first step. The granularity of tissue-specific features and organ-based immunity will further increase by integrating the information obtained by even more sophisticated technologies in the near future. The dots are coming together to generate a high-resolution picture, which will define new standards in transplantation immunology.


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