scholarly journals γδ-Thymocyte Maturation and Emigration

2021 ◽  
Author(s):  
K. Joannou ◽  
D.P. Golec ◽  
H. Wang ◽  
L.M. Henao-Caviedes ◽  
J.F. May ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Γδ T Cells ◽  
Cell Development ◽  
Γδ T Cell ◽  
Fetal Thymus ◽  
Adult Mice ◽  
The Relationship ◽  
Adult Thymus

AbstractThe thymus is the site of both αβ and γδ-T cell development. After several unique waves of γδ-T cells are generated in, and exported from, the fetal/neonatal thymus, the adult thymus continues to produce a stream of γδ-T cells throughout life. One intriguing feature of γδ T cell development is the coordination of differentiation and acquisition of effector function within the fetal thymus, however, it is less clear whether this paradigm holds true in adult animals. To investigate the relationship between maturation and time since V(D)J recombination in adult-derived γδ-thymocytes, we used the Rag2pGFP model. Immature (CD24+) γδ-thymocytes expressed high levels of GFP while only a small minority of mature (CD24-) γδ-thymocytes were GFP+. Similarly, most GFP+ γδ-splenocytes were immature, while some were mature. Analysis of γδ-recent thymic emigrants (RTEs) indicated that most γδ-T cell RTEs were CD24+ and GFP+ and adoptive transfer experiments showed that immature γδ-thymocytes could be maintained in the periphery for at least 3 days over which time they matured. With respect to the mature γδ-thymocytes that were GFP-, parabiosis experiments demonstrated that mature γδ-T cells did not recirculate from the periphery. Instead, a population of mature γδ-thymocytes remained resident in the thymus for at least 60 days while mature γδ-thymocytes derived solely from adult hematopoiesis were mostly lost from the thymus within 60 days. Collectively, these data demonstrate two streams of actively developing γδ-T cells in adult mice: an immature subset that quickly leaves the thymus and matures in the periphery, and one that completes maturation within the thymus over a longer period of time. Furthermore, there is a fetal-derived and heterogeneous population of resident γδ-thymocytes of unknown functional importance.

scholarly journals Different composition of the human and the mouse γδ T cell receptor explains different phenotypes of CD3γ and CD3δ immunodeficiencies

2007 ◽  
Vol 204 (11) ◽  
pp. 2537-2544 ◽  
Author(s):  
Gabrielle M. Siegers ◽  
Mahima Swamy ◽  
Edgar Fernández-Malavé ◽  
Susana Minguet ◽  
Sylvia Rathmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Development ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Cell Development ◽  
Γδ T Cell ◽  
Deficient Mice ◽  
Γδ T Cell Receptor

The γδ T cell receptor for antigen (TCR) comprises the clonotypic TCRγδ, the CD3 (CD3γε and/or CD3δε), and the ζζ dimers. γδ T cells do not develop in CD3γ-deficient mice, whereas human patients lacking CD3γ have abundant peripheral blood γδ T cells expressing high γδ TCR levels. In an attempt to identify the molecular basis for these discordant phenotypes, we determined the stoichiometries of mouse and human γδ TCRs using blue native polyacrylamide gel electrophoresis and anti-TCR–specific antibodies. The γδ TCR isolated in digitonin from primary and cultured human γδ T cells includes CD3δ, with a TCRγδCD3ε2δγζ2 stoichiometry. In CD3γ-deficient patients, this may allow substitution of CD3γ by the CD3δ chain and thereby support γδ T cell development. In contrast, the mouse γδ TCR does not incorporate CD3δ and has a TCRγδCD3ε2γ2ζ2 stoichiometry. CD3γ-deficient mice exhibit a block in γδ T cell development. A human, but not a mouse, CD3δ transgene rescues γδ T cell development in mice lacking both mouse CD3δ and CD3γ chains. This suggests important structural and/or functional differences between human and mouse CD3δ chains during γδ T cell development. Collectively, our results indicate that the different γδ T cell phenotypes between CD3γ-deficient humans and mice can be explained by differences in their γδ TCR composition.

Coordination between CCR7- and CCR9-mediated chemokine signals in prevascular fetal thymus colonization

Blood ◽  
2006 ◽  
Vol 108 (8) ◽  
pp. 2531-2539 ◽  
Author(s):  
Cunlan Liu ◽  
Fumi Saito ◽  
Zhijie Liu ◽  
Yu Lei ◽  
Shoji Uehara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Progenitor Cells ◽  
Chemokine Receptors ◽  
T Cell Development ◽  
Γδ T Cells ◽  
Cell Development ◽  
Fetal Thymus ◽  
Before And After

AbstractThymus seeding by T-lymphoid progenitor cells is a prerequisite for T-cell development. However, molecules guiding thymus colonization and their roles before and after thymus vascularization are unclear. Here we show that mice doubly deficient for chemokine receptors CCR7 and CCR9 were defective specifically in fetal thymus colonization before, but not after, thymus vascularization. The defective prevascular fetal thymus colonization was followed by selective loss of the first wave of T-cell development generating epidermal Vγ3+ γδ T cells. Unexpectedly, CCL21, a CCR7 ligand, was expressed not by Foxn1-dependent thymic primordium but by Gcm2-dependent parathyroid primordium, whereas CCL25, a CCR9 ligand, was predominantly expressed by Foxn1-dependent thymic primordium, revealing the role of the adjacent parathyroid in guiding fetal thymus colonization. These results indicate coordination between Gcm2-dependent parathyroid and Foxn1-dependent thymic primordia in establishing CCL21/CCR7- and CCL25/CCR9-mediated chemokine guidance essential for prevascular fetal thymus colonization.

Sustained Notch1 signaling instructs the earliest human intrathymic precursors to adopt a γδ T-cell fate in fetal thymus organ culture

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2444-2451 ◽  
Author(s):  
Marina García-Peydró ◽  
Virginia G. de Yébenes ◽  
María L. Toribio
Keyword(s):  
T Cells ◽  
T Cell ◽  
Organ Culture ◽  
Cell Fate ◽  
Γδ T Cells ◽  
Retroviral Vectors ◽  
Γδ T Cell ◽  
Fetal Thymus ◽  
Notch1 Signaling ◽  
The Impact

Abstract Notch1 activity is essential for the specification of T-lineage fate in hematopoietic progenitors. Once the T-cell lineage is specified, T-cell precursors in the thymus must choose between αβ and γδ lineages. However, the impact of Notch1 signaling on intrathymic pro-T cells has not been addressed directly. To approach this issue, we used retroviral vectors to express constitutively active Notch1 in human thymocyte progenitors positioned at successive developmental stages, and we followed their differentiation in fetal thymus organ culture (FTOC). Here we show that sustained Notch1 signaling impairs progression to the double-positive (DP) stage and efficiently diverts the earliest thymic progenitors from the main αβ T-cell pathway toward development of γδ T cells. The impact of Notch1 signaling on skewed γδ production decreases progressively along intrathymic maturation and is restricted to precursor stages upstream of the pre-T-cell receptor checkpoint. Close to and beyond that point, Notch1 is not further able to instruct γδ cell fate, but promotes an abnormal expansion of αβ-committed thymocytes. These results stress the stage-specific impact of Notch1 signaling in intrathymic differentiation and suggest that regulation of Notch1 activity at defined developmental windows is essential to control αβ versus γδ T-cell development and to avoid deregulated expansion of αβ-lineage cells. (Blood. 2003;102:2444-2451)

Separate Ways

2007 ◽  
Vol 2007 (369) ◽  
pp. tw23-tw23
Author(s):  
Stephen Simpson
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Cell Fate ◽  
T Cell Development ◽  
Γδ T Cells ◽  
Anatomical Location ◽  
Γδ T Cell ◽  
Link Type ◽  
Common Precursor

Two dominant lineages of T cells (αβ and γδ T cells) are highly distinct in function and anatomical location yet share a common precursor within the thymus. Exactly how one cell fate is decided over another remains unresolved. Melichar et al. present evidence that selection to the γδ T cell branch in the thymus is controlled by the transcription factor SOX13, which supports and possibly even initiates γδ T cell development while opposing differentiation of their αβ T cell brethren. The authors noted that SOX13 inhibited an important effector of the central T cell developmental signaling pathway mediated by the Wnt protein. H. J. Melichar, K. Narayan, S. D. Der, Y. Hiraoka, N. Gardiol, G. Jeannet, W. Held, C. A. Chambers, J. Kang, Regulation of γδ versus αβ T lymphocyte differentiation by the transcription factor SOX13. Science315, 230-233 (2007). [Abstract][Full Text]

scholarly journals Genetic models reveal origin, persistence and non-redundant functions of IL-17–producing γδ T cells

2018 ◽  
Vol 215 (12) ◽  
pp. 3006-3018 ◽  
Author(s):  
Inga Sandrock ◽  
Annika Reinhardt ◽  
Sarina Ravens ◽  
Christoph Binz ◽  
Anneke Wilharm ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Diphtheria Toxin ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Fetal Thymus ◽  
Effector Cells ◽  
Cell Functions ◽  
Ifn Γ ◽  
Redundant Functions

γδ T cells are highly conserved in jawed vertebrates, suggesting an essential role in the immune system. However, γδ T cell–deficient Tcrd−/− mice display surprisingly mild phenotypes. We hypothesized that the lack of γδ T cells in constitutive Tcrd−/− mice is functionally compensated by other lymphocytes taking over genuine γδ T cell functions. To test this, we generated a knock-in model for diphtheria toxin–mediated conditional γδ T cell depletion. In contrast to IFN-γ–producing γδ T cells, IL-17–producing γδ T cells (Tγδ17 cells) recovered inefficiently after depletion, and their niches were filled by expanding Th17 cells and ILC3s. Complementary genetic fate mapping further demonstrated that Tγδ17 cells are long-lived and persisting lymphocytes. Investigating the function of γδ T cells, conditional depletion but not constitutive deficiency protected from imiquimod-induced psoriasis. Together, we clarify that fetal thymus-derived Tγδ17 cells are nonredundant local effector cells in IL-17–driven skin pathology.

scholarly journals Requirement of dendritic cells and B cells in the clonal deletion of Mls-reactive T cells in the thymus.

1991 ◽  
Vol 173 (3) ◽  
pp. 539-547 ◽  
Author(s):  
O Mazda ◽  
Y Watanabe ◽  
J Gyotoku ◽  
Y Katsura
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Clonal Deletion ◽  
Fetal Thymus ◽  
Effector Cells

The present study was performed to identify cells responsible for the elimination of T cells reactive with minor lymphocyte-stimulating (Mls) antigens during T cell development. Experiments were carried out in a fetal thymus organ culture (FTOC) system. To examine the tolerance-inducing activity, various populations of cells from adult CBA/J (Mls-1a) mice were injected into deoxyguanosine (dGuo)-treated FTOC of C3H/He (Mls-1b) mice with a microinjector, and 2 d later, the thymus lobes were injected with fetal thymus cells from C3H/He mice as T cell precursors. After 14 d of cultivation, cells were harvested and assayed for the expression of the T cell receptor V beta 6 element. The absence or marked reduction of T cells expressing V beta 6 at high levels (V beta 6high) was regarded as indicating the deletion of Mls-1a-reactive T cells. T cell-depleted populations of thymic as well as splenic cells from CBA/J mice were able to induce clonal deletion. Further characterization of the effector cells was carried out by fractionating the spleen cells before injecting them into dGuo-FTOC. None of the dish-adherent population, dish-nonadherent population, or purified B cells alone were able to induce clonal deletion, whereas the addition of purified B cells to adherent cells restored tolerance inducibility. It was further shown that a combination of CBA/J B cells and C3H/He dendritic cells was effective in eliminating Mls-reactive clones. These results indicate that for the deletion of clones reactive with Mls antigens during T cell development in the thymus, both DC and B cells are required.

scholarly journals Visualization of the earliest steps of γδ T cell development in the adult thymus

2006 ◽  
Vol 7 (9) ◽  
pp. 995-1003 ◽  
Author(s):  
Immo Prinz ◽  
Amandine Sansoni ◽  
Adrien Kissenpfennig ◽  
Laurence Ardouin ◽  
Marie Malissen ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Γδ T Cell ◽  
Adult Thymus

An early decrease in Notch activation is required for human TCR-αβ lineage differentiation at the expense of TCR-γδ T cells

Blood ◽  
2009 ◽  
Vol 113 (13) ◽  
pp. 2988-2998 ◽  
Author(s):  
Inge Van de Walle ◽  
Greet De Smet ◽  
Magda De Smedt ◽  
Bart Vandekerckhove ◽  
Georges Leclercq ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Notch Signaling ◽  
Target Genes ◽  
T Cell Development ◽  
Γδ T Cells ◽  
Cell Development ◽  
Lineage Differentiation ◽  
Human T Cell ◽  
Notch Activation

Abstract Although well characterized in the mouse, the role of Notch signaling in the human T-cell receptor αβ (TCR-αβ) versus TCR-γδ lineage decision is still unclear. Although it is clear in the mouse that TCR-γδ development is less Notch dependent compared with TCR-αβ differentiation, retroviral overexpression studies in human have suggested an opposing role for Notch during human T-cell development. Using the OP9-coculture system, we demonstrate that changes in Notch activation are differentially required during human T-cell development. High Notch activation promotes the generation of T-lineage precursors and γδ T cells but inhibits differentiation toward the αβ lineage. Reducing the amount of Notch activation rescues αβ-lineage differentiation, also at the single-cell level. Gene expression analysis suggests that this is mediated by differential sensitivities of Notch target genes in response to changes in Notch activation. High Notch activity increases DTX1, NRARP, and RUNX3 expression, genes that are down-regulated during αβ-lineage differentiation. Furthermore, increased interleukin-7 levels cannot compensate for the Notch dependent TCR-γδ development. Our results reveal stage-dependent molecular changes in Notch signaling that are critical for normal human T-cell development and reveal fundamental molecular differences between mouse and human.

scholarly journals MTOR Signaling and Metabolism in Early T Cell Development

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 728
Author(s):  
Guy Werlen ◽  
Ritika Jain ◽  
Estela Jacinto
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Fate ◽  
T Cell Activation ◽  
T Cell Development ◽  
Γδ T Cells ◽  
Cell Development ◽  
Mtor Signaling ◽  
Metabolic Reprogramming ◽  
Metabolic Remodeling

The mechanistic target of rapamycin (mTOR) controls cell fate and responses via its functions in regulating metabolism. Its role in controlling immunity was unraveled by early studies on the immunosuppressive properties of rapamycin. Recent studies have provided insights on how metabolic reprogramming and mTOR signaling impact peripheral T cell activation and fate. The contribution of mTOR and metabolism during early T-cell development in the thymus is also emerging and is the subject of this review. Two major T lineages with distinct immune functions and peripheral homing organs diverge during early thymic development; the αβ- and γδ-T cells, which are defined by their respective TCR subunits. Thymic T-regulatory cells, which have immunosuppressive functions, also develop in the thymus from positively selected αβ-T cells. Here, we review recent findings on how the two mTOR protein complexes, mTORC1 and mTORC2, and the signaling molecules involved in the mTOR pathway are involved in thymocyte differentiation. We discuss emerging views on how metabolic remodeling impacts early T cell development and how this can be mediated via mTOR signaling.

scholarly journals Constrained TCRγδ-associated Syk activity engages PI3K to facilitate thymic development of IL-17A–secreting γδ T cells

2021 ◽  
Vol 14 (692) ◽  
pp. eabc5884
Author(s):  
Nital Sumaria ◽  
Stefania Martin ◽  
Daniel J. Pennington
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Fate ◽  
Γδ T Cells ◽  
Gene Expression Signature ◽  
Cell Receptor ◽  
Cell Development ◽  
Type I ◽  
Γδ T Cell ◽  
Thymic Development

Murine γδ17 cells, which are T cells that bear the γδ T cell receptor (TCRγδ) and secrete interleukin-17A (IL-17A), are generated in the thymus and are critical for various immune responses. Although strong TCRγδ signals are required for the development of interferon-γ (IFN-γ)–secreting γδ cells (γδIFN cells), the generation of γδ17 cells requires weaker TCRγδ signaling. Here, we demonstrated that constrained activation of the kinase Syk downstream of TCRγδ was required for the thymic development of γδ17 cells. Increasing or decreasing Syk activity by stimulating TCRγδ or inhibiting Syk, respectively, substantially reduced γδ17 cell numbers. This delimited Syk activity optimally engaged the phosphoinositide 3-kinase (PI3K)–Akt signaling pathway, which maintained the expression of master regulators of the IL-17 program, RORγt and c-Maf. Inhibition of PI3K not only abrogated γδ17 cell development but also augmented the development of a distinct, previously undescribed subset of γδ T cells. These CD8+Ly6a+ γδ T cells had a type-I IFN gene expression signature and expanded in response to stimulation with IFN-β. Collectively, these studies elucidate how weaker TCRγδ signaling engages distinct signaling pathways to specify the γδ17 cell fate and identifies a role for type-I IFNs in γδ T cell development.

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