Graft-versus-host disease is locally maintained in target tissues by resident progenitor-like T cells

Sacirbegovic, Faruk; Günther, Matthias; Greco, Alessandro; Zhao, Daqiang; Wang, Xi; Zhou, Meng; Rosenberger, Sarah; Oberbarnscheidt, Martin H.; Held, Werner; McNiff, Jennifer M.; Jain, Dhanpat; Höfer, Thomas; Shlomchik, Warren D.

doi:10.1016/j.immuni.2023.01.003

Cited by 21 publications

(17 citation statements)

References 62 publications

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“…This unsupervised approach revealed clustering of similar anatomic tissues (duodenum, colon, and ileum), with the dendrograms highlighting in particular the GI tract at day 14 after transplant (Fig. 6E); tissues appeared more similar to each other at day 7 compared with day 14, consistent with recently published data ( 55 ).…”

Section: Resultssupporting

confidence: 89%

Tissue-specific features of the T cell repertoire after allogeneic hematopoietic cell transplantation in human and mouse

DeWolf,

Elhanati,

Nichols

et al. 2023

Sci. Transl. Med.

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T cells are the central drivers of many inflammatory diseases, but the repertoire of tissue-resident T cells at sites of pathology in human organs remains poorly understood. We examined the site-specificity of T cell receptor (TCR) repertoires across tissues (5 to 18 tissues per patient) in prospectively collected autopsies of patients with and without graft-versus-host disease (GVHD), a potentially lethal tissue-targeting complication of allogeneic hematopoietic cell transplantation, and in mouse models of GVHD. Anatomic similarity between tissues was a key determinant of TCR repertoire composition within patients, independent of disease or transplant status. The T cells recovered from peripheral blood and spleens in patients and mice captured a limited portion of the TCR repertoire detected in tissues. Whereas few T cell clones were shared across patients, motif-based clustering revealed shared repertoire signatures across patients in a tissue-specific fashion. T cells at disease sites had a tissue-resident phenotype and were of donor origin based on single-cell chimerism analysis. These data demonstrate the complex composition of T cell populations that persist in human tissues at the end stage of an inflammatory disorder after lymphocyte-directed therapy. These findings also underscore the importance of studying T cell in tissues rather than blood for tissue-based pathologies and suggest the tissue-specific nature of both the endogenous and posttransplant T cell landscape.

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Section: Resultssupporting

confidence: 89%

Tissue-specific features of the T cell repertoire after allogeneic hematopoietic cell transplantation in human and mouse

DeWolf,

Elhanati,

Nichols

et al. 2023

Sci. Transl. Med.

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“…44 , 45 , 46 Koyama et al 46 showed that the majority of dominant TCRs found in GVHD-affected skin tissues were also detectable in blood, including the TCR of 1 of 2 confirmed alloreactive T-cell clones. However, Sacirbegovic et al 47 showed in mice that TCR repertoires in affected GVHD tissues compared with blood increasingly diverge in time because of T-cell influx from blood in early GVHD and subsequent maintenance by tissue-resident progenitor-like T cells in late GVHD. We often analyzed samples before the onset of clinically diagnosed GVHD, which increases the chance to detect MiHA-specific T cells before homing to tissues.…”

Section: Discussionmentioning

confidence: 99%

Expanding the repertoire reveals recurrent, cryptic, and hematopoietic HLA class I minor histocompatibility antigens

Fuchs,

van de Meent,

Honders

et al. 2024

Blood

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Allogeneic stem cell transplantation (alloSCT) is a curative treatment for hematological malignancies. After HLA-matched alloSCT, anti-tumor immunity is caused by donor T cells recognizing polymorphic peptides, designated minor histocompatibility antigens (MiHAs), that are presented by HLA on malignant patient cells. However, T cells often target MiHAs on healthy non-hematopoietic tissues of patients, thereby inducing side effects known as Graft-versus-Host Disease. Here, we aimed to identify the dominant repertoire of HLA-I-restricted MiHAs to enable strategies to predict, monitor or modulate immune responses after alloSCT. To systematically identify novel MiHAs by genome-wide association screening, T-cell clones were isolated from 39 transplanted patients and tested for reactivity against 191 EBV-B cell lines of the 1000 Genomes Project. By discovering 81 new MiHAs, we more than doubled the antigen repertoire to 159 MiHAs and demonstrated that, despite many genetic differences between patients and donors, often the same MiHAs are targeted in multiple patients. Furthermore, we showed that one quarter of the antigens are cryptic, i.e. translated from unconventional open reading frames, for example long non-coding RNAs, showing that these antigen types are relevant targets in natural immune responses. Finally, using single cell RNA-seq data, we analyzed tissue expression of MiHA-encoding genes to explore their potential role in clinical outcome, and characterized 11 new hematopoietic-restricted MiHAs as potential targets for immunotherapy. In conclusion, we expanded the repertoire of HLA-I-restricted MiHAs and identified recurrent, cryptic and hematopoietic-restricted antigens, which are fundamental to predict, follow or manipulate immune responses to improve clinical outcome after alloSCT.

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“…Using TCR sequencing, a recent report described that certain TCR clones expand more in barrier sites compared to circulatory memory populations, indicating that the TCR pool in circulation is not representative of that seen in tissues 61 —an observation that has important implications in numerous areas, such as vaccine design and boosting strategies 63 . This finding is corroborated by a report using clonal tracing of T‐cell clones that showed that graft‐versus‐host disease (GvHD) in a murine model is maintained by expansion of a tissue‐residing TCF1 + subpopulation and not by recruitment of T cells from secondary lymphoid organs or the blood 64 . Furthermore, in humans, TCR clones for CD4 + T RM cells segregated between the barrier tissues with only minimal overlap between the skin, lung, and jejunum, where CD4 + T‐cell clones are less disseminated and more site‐specific compared to CD8 + T‐cell clones 61 .…”

Section: Intertissue Heterogeneitymentioning

confidence: 93%

“…63 This finding is corroborated by a report using clonal tracing of T-cell clones that showed that graft-versus-host disease (GvHD) in a murine model is maintained by expansion of a tissue-residing TCF1 + subpopulation and not by recruitment of T cells from secondary lymphoid organs or the blood. 64 Furthermore, in humans, TCR clones for CD4 + T RM cells segregated between the barrier tissues with only minimal overlap between the skin, lung, and jejunum, where CD4 + T-cell clones are less disseminated and more site-specific compared to CD8 + T-cell clones. 61 It is possible that this clonal segregation is a result of different infections or pathogens that T cells encounter at these three distinct barrier sites, but the possibility that certain TCR clones preferentially give rise to T RM cells in a specific organ cannot yet be ruled out.…”

Section: Clonal Relationships Between Circulatory and Tissue-resident...mentioning

confidence: 99%

Insights into phenotypic and functional CD8⁺ T_RM heterogeneity

Heeg

Goldrath

2023

Immunological Reviews

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Summary Cytotoxic CD8+ T cells recognize and eliminate infected or cancerous cells. A subset of CD8+ memory T cells called tissue‐resident memory T cells (TRM) resides in peripheral tissues, monitors the periphery for pathogen invasion, and offers a rapid and potent first line of defense at potential sites of re‐infection. TRM cells are found in almost all tissues and are transcriptionally and epigenetically distinct from circulating memory populations, which shows their ability to acclimate to the tissue environment to allow for long‐term survival. Recent work and the broader availability of single‐cell profiling have highlighted TRM heterogeneity among different tissues, as well as identified specialized subsets within individual tissues, that are time and infection dependent. TRM cell phenotypic and transcriptional heterogeneity has implications for understanding TRM function and longevity. This review aims to summarize and discuss the latest findings on CD8+ TRM heterogeneity using single‐cell molecular profiling and explore the potential implications for immune protection and the design of immune therapies.

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Graft-versus-host disease is locally maintained in target tissues by resident progenitor-like T cells

Cited by 21 publications

References 62 publications

Tissue-specific features of the T cell repertoire after allogeneic hematopoietic cell transplantation in human and mouse

Tissue-specific features of the T cell repertoire after allogeneic hematopoietic cell transplantation in human and mouse

Expanding the repertoire reveals recurrent, cryptic, and hematopoietic HLA class I minor histocompatibility antigens

Insights into phenotypic and functional CD8⁺ T_RM heterogeneity

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Graft-versus-host disease is locally maintained in target tissues by resident progenitor-like T cells

Cited by 21 publications

References 62 publications

Tissue-specific features of the T cell repertoire after allogeneic hematopoietic cell transplantation in human and mouse

Tissue-specific features of the T cell repertoire after allogeneic hematopoietic cell transplantation in human and mouse

Expanding the repertoire reveals recurrent, cryptic, and hematopoietic HLA class I minor histocompatibility antigens

Insights into phenotypic and functional CD8+ TRM heterogeneity

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Product

Resources

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Insights into phenotypic and functional CD8⁺ T_RM heterogeneity