Spatial Mapping of Thymic Stromal Microenvironments Reveals Unique Features Influencing T Lymphoid Differentiation

Griffith, Ann V.; Fallahi, Mohammad; Nakase, Hiroshi; Gosink, Mark; Young, Brandon; Petrie, Howard T.

doi:10.1016/j.immuni.2009.09.024

Cited by 72 publications

(94 citation statements)

References 60 publications

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“…Several lines of evidence indicate that these cytokines are available to developing γδ T cells in the thymus. Previous work by Petrie and colleagues showed that IL-1β and IL-23 are expressed by mTECs at comparable levels to IL-7 42 . Moreover, specific subsets of thymic γδ T cells and a population of CD4 + T cells express high levels of IL-21R, during the appropriate ontological window of time to affect γδ17 development (www.immgen.org) 43 , plus a subset of IL-21 expressing thymocytes was recently reported 44 .…”

Section: Resultsmentioning

confidence: 94%

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

Zarin

Chen

et al. 2018

Immunol Cell Biol

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γδ T-cells perform a wide range of tissue and disease specific functions that are dependent on the effector cytokines produced by these cells. However, the aggregate signals required for the development of interferon-γ (IFNγ) and interleukin-17 (IL-17) producing γδ T-cells remain unknown. Here, we define the cues involved in the functional programming of γδ T-cells, by examining the roles of T-cell receptor (TCR), Notch, and cytokine-receptor signaling. KN6 γδTCR-transduced Rag2−/− T-cell progenitors were cultured on stromal cells variably expressing TCR and Notch ligands, supplemented with different cytokines. We found that distinct combinations of these signals are required to program IFNγ versus IL-17 producing γδ T cell subsets, with Notch and weak TCR ligands optimally enabling development of γδ17 cells in the presence of IL-1β, IL-21 and IL-23. Notably, these cytokines were also shown to be required for the intrathymic development of γδ17 cells. Together, this work provides a framework of how signals downstream of TCR, Notch and cytokine receptors integrate to program the effector function of IFNγ and IL-17 producing γδ T-cell subsets.

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Section: Resultsmentioning

confidence: 94%

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

Zarin

Chen

et al. 2018

Immunol Cell Biol

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“…Age-related thymic degeneration is a significant impediment in cancer patients undergoing HSCT because the conditioning regimens damage already reduced stromal cell niches in recipient thymi (41)(42)(43)(44). In elderly patients, the impaired T-cell reconstitution due to thymic damage after HSCT results in prolonged posttransplant T-cell deficiency and significant mortality and morbidity (43).…”

Section: R F G F O H T O L K -B 2 R F G F 3 R F G F 4 R F G F 2 F G Fmentioning

confidence: 99%

Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution

Youm

Horváth

Mangelsdorf

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

101

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Age-related thymic degeneration is associated with loss of naïve T cells, restriction of peripheral T-cell diversity, and reduced healthspan due to lower immune competence. The mechanistic basis of age-related thymic demise is unclear, but prior evidence suggests that caloric restriction (CR) can slow thymic aging by maintaining thymic epithelial cell integrity and reducing the generation of intrathymic lipid. Here we show that the prolongevity ketogenic hormone fibroblast growth factor 21 (FGF21), a member of the endocrine FGF subfamily, is expressed in thymic stromal cells along with FGF receptors and its obligate coreceptor, βKlotho. We found that FGF21 expression in thymus declines with age and is induced by CR. Genetic gain of FGF21 function in mice protects against agerelated thymic involution with an increase in earliest thymocyte progenitors and cortical thymic epithelial cells. Importantly, FGF21 overexpression reduced intrathymic lipid, increased perithymic brown adipose tissue, and elevated thymic T-cell export and naïve T-cell frequencies in old mice. Conversely, loss of FGF21 function in middle-aged mice accelerated thymic aging, increased lethality, and delayed T-cell reconstitution postirradiation and hematopoietic stem cell transplantation (HSCT). Collectively, FGF21 integrates metabolic and immune systems to prevent thymic injury and may aid in the reestablishment of a diverse T-cell repertoire in cancer patients following HSCT.

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“…Recently, a similar approach was used to analyze the gene expression of the thymic stromal microenvironments [45]. Data sets obtained from dissected FDC networks were compared with those of sorted B cells.…”

Section: Microarray Analysismentioning

confidence: 99%

In silico subtraction approach reveals a close lineage relationship between follicular dendritic cells and BP3^hi stromal cells isolated from SCID mice

et al. 2010

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Organization of the stromal compartments in secondary lymphoid tissue is a prerequisite for an efficient immune reaction. In particular, follicular dendritic cells (FDC) are pivotal for the activation and differentiation of B cells. To investigate the development of FDC, FDC together with tightly associated B cells (FDC networks) were micro-dissected from frozen tissue sections and follicular B cells were sorted by FACS. Using an in silico subtraction approach, gene expression of FDC was determined and compared with that of follicular stromal cells microdissected from the spleen of SCID mice. Nearly 90% of the FDC genes were expressed in follicular stromal cells of the SCID mouse, providing further evidence that FDC develop from the residual network of reticular cells. Thus, it suggests that rather minor modifications in the gene expression profile are sufficient for differentiation into mature FDC. The analysis of different immune-deficient mouse strains shows that a complex pattern of gene regulation controls the development of residual stromal cells into mature FDC. The in silico subtraction approach provides a molecular framework within which to determine the diverse roles of FDC in support of B cells and to investigate the differentiation of FDC from their mesenchymal precursor cells. [1][2][3][4]. The network of FDC is a micro-environment required for the survival of follicular B cells and is also a prerequisite for an efficient GC reaction. At the early stage of GC development FDC support B-cell proliferation, whereas at the later stages FDC have an important function in the selection and differentiation of high affinity B cells to memory and plasma cells [1,5].Although FDC are crucial for B-cell development, our knowledge of FDC transcriptional activity remains marginal. FDC are fragile cells and are tightly associated with B cells -properties that have thus far hampered the isolation of pure FDC populations [6][7]. To overcome these problems, FDC lines have been established, however, as these cells are maintained over several weeks in culture, their phenotype no longer reflects the in vivo situation [8][9][10][11][12][13]. A number of different approaches for the enrichment and gene expression analysis of FDC have been shown to be more representative of the in vivo situation [6,8,11].From a number of experiments, it is apparent that FDC are a highly specialized subset of reticular cells [14][15][16][17][18]. Using BP3, an ectoenzyme of the NAD glycohydrolase family, as a marker antigen for the splenic reticular network of stromal cells, one can distinguish the reticulum cells in the B-cell area from those in the T-cell zone. High expression of BP3 defines the follicle, the area to which B cells To identify molecular markers defining a developmental relationship between mature FDC and the BP3 hi reticular cells of SCID mice, gene expression profiles were determined. Using an in silico subtraction approach, we were able to identify a novel set of genes that showed specific expression in FDC. When gene ex...

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Spatial Mapping of Thymic Stromal Microenvironments Reveals Unique Features Influencing T Lymphoid Differentiation

Cited by 72 publications

References 60 publications

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution

In silico subtraction approach reveals a close lineage relationship between follicular dendritic cells and BP3^hi stromal cells isolated from SCID mice

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Spatial Mapping of Thymic Stromal Microenvironments Reveals Unique Features Influencing T Lymphoid Differentiation

Cited by 72 publications

References 60 publications

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution

In silico subtraction approach reveals a close lineage relationship between follicular dendritic cells and BP3hi stromal cells isolated from SCID mice

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In silico subtraction approach reveals a close lineage relationship between follicular dendritic cells and BP3^hi stromal cells isolated from SCID mice