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.

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.

scholarly journals Essential and Partially Overlapping Role of CD3γ and CD3δ for Development of αβ and γδ T Lymphocytes

1998 ◽  
Vol 188 (7) ◽  
pp. 1375-1380 ◽  
Author(s):  
Baoping Wang ◽  
Ninghai Wang ◽  
Mariolina Salio ◽  
Arlene Sharpe ◽  
Deborah Allen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Gene Knockout ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Γδ T Cell ◽  
Thymic Development ◽  
Gene Knockout Mice

CD3γ and CD3δ are two highly related components of the T cell receptor (TCR)–CD3 complex which is essential for the assembly and signal transduction of the T cell receptor on mature T cells. In gene knockout mice deficient in either CD3δ or CD3γ, early thymic development mediated by pre-TCR was either undisturbed or severely blocked, respectively, and small numbers of TCR-αβ+ T cells were detected in the periphery of both mice. γδ T cell development was either normal in CD3δ−/− mice or partially blocked in CD3γ−/− mice. To examine the collective role of CD3γ and CD3δ in the assembly and function of pre-TCR and in the development of γδ T cells, we generated a mouse strain with a disruption in both CD3γ and CD3δ genes (CD3γδ−/−). In contrast to mice deficient in either CD3γ or CD3δ chains, early thymic development mediated by pre-TCR is completely blocked, and TCR-αβ+ or TCR-γδ+ T cells were absent in the CD3γδ−/− mice. Taken together, these studies demonstrated that CD3γ and CD3δ play an essential, yet partially overlapping, role in the development of both αβ and γδ T cell lineages.

scholarly journals αβ-T Cells Engineered to Express γδ-T Cell Receptors Can Kill Neuroblastoma Organoids Independent of MHC-I Expression

2021 ◽  
Vol 11 (9) ◽  
pp. 923
Author(s):  
Josephine G. M. Strijker ◽  
Ronja Pscheid ◽  
Esther Drent ◽  
Jessica J. F. van der Hoek ◽  
Bianca Koopmans ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transcriptional Profiling ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Target Cells ◽  
Γδ T Cell ◽  
Mhc I ◽  
Organization Analysis ◽  
Αβ T Cells

Currently ~50% of patients with a diagnosis of high-risk neuroblastoma will not survive due to relapsing or refractory disease. Recent innovations in immunotherapy for solid tumors are highly promising, but the low MHC-I expression of neuroblastoma represents a major challenge for T cell-mediated immunotherapy. Here, we propose a novel T cell-based immunotherapy approach for neuroblastoma, based on the use of TEG002, αβ-T cells engineered to express a defined γδ-T cell receptor, which can recognize and kill target cells independent of MHC-I. In a co-culture killing assay, we showed that 3 out of 6 neuroblastoma organoids could activate TEG002 as measured by IFNγ production. Transcriptional profiling showed this effect correlates with an increased activity of processes involved in interferon signaling and extracellular matrix organization. Analysis of the dynamics of organoid killing by TEG002 over time confirmed that organoids which induced TEG002 activation were efficiently killed independent of their MHC-I expression. Of note, efficacy of TEG002 treatment was superior to donor-matched untransduced αβ-T cells or endogenous γδ-T cells. Our data suggest that TEG002 may be a promising novel treatment option for a subset of neuroblastoma patients.

scholarly journals Activation-induced Modification in the CD3 Complex of the γδ T Cell Receptor

2002 ◽  
Vol 196 (10) ◽  
pp. 1355-1361 ◽  
Author(s):  
Sandra M. Hayes ◽  
Karen Laky ◽  
Dalal El-Khoury ◽  
Dietmar J. Kappes ◽  
B.J. Fowlkes ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Intraepithelial Lymphocytes ◽  
Subunit Composition ◽  
Γδ T Cell ◽  
Receptor Complexes ◽  
Functional Consequences

The T cell antigen receptor complexes expressed on αβ and γδ T cells differ not only in their respective clonotypic heterodimers but also in the subunit composition of their CD3 complexes. The γδ T cell receptors (TCRs) expressed on ex vivo γδ T cells lack CD3δ, whereas αβ TCRs contain CD3δ. While this result correlates with the phenotype of CD3δ−/− mice, in which γδ T cell development is unaffected, it is inconsistent with the results of previous studies reporting that CD3δ is a component of the γδ TCR. Since earlier studies examined the subunit composition of γδ TCRs expressed on activated and expanded peripheral γδ T cells or γδ TCR+ intestinal intraepithelial lymphocytes, we hypothesized that activation and expansion may lead to changes in the CD3 subunit composition of the γδ TCR. Here, we report that activation and expansion do in fact result in the inclusion of a protein, comparable in mass and mobility to CD3δ, in the γδ TCR. Further analyses revealed that this protein is not CD3δ, but instead is a differentially glycosylated form of CD3γ. These results provide further evidence for a major difference in the subunit composition of αβ- and γδ TCR complexes and raise the possibility that modification of CD3γ may have important functional consequences in activated γδ T cells.

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 Evidence That γδ versus αβ T Cell Fate Determination Is Initiated Independently of T Cell Receptor Signaling

2001 ◽  
Vol 193 (6) ◽  
pp. 689-698 ◽  
Author(s):  
Joonsoo Kang ◽  
Ariane Volkmann ◽  
David H. Raulet
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Fate ◽  
T Cell Receptor ◽  
Gene Rearrangement ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Developmental Potential ◽  
Cd8 Cells ◽  
Interleukin 7

Two types of T cells, αβ and γδ, develop in vertebrates. How these two T cell lineages arise from a common thymic T progenitor is poorly understood. Differentiation of αβ lineage T cells requires the surrogate α chain (pTα), which associates with the T cell receptor (TCR) β chain to form the pre-TCR. γδ lineage development does not appear to involve an obligatory surrogate chain, but instead requires productive rearrangement and expression of both TCR γ and δ genes. It has been proposed that the quality of signals transmitted by the pre-TCR and γδ TCR are distinct and that these “instructive” signals determine the lineage fate of an uncommitted progenitor cell. Here we show that the thymic T progenitor cells (CD25+CD44+c-kit+CD3−CD4−CD8− thymocytes, termed pro-T cells) from young adult mice that have yet to express TCRs can be subdivided based on interleukin 7 receptor (IL-7R) expression. These subsets exhibit differential potential to develop into γδ versus αβ lineage (CD4+CD8+ cells) in the thymus. Upon intrathymic injection, IL-7Rneg-lo pro-T cells generated a 13-fold higher ratio of αβ lineage to γδ lineage cells than did IL-7R+ pro-T cells. Much of this difference was due to a fivefold greater potential of IL-7R+ pro-T cells to develop into TCR-γδ T cells. Evidence indicates that this biased developmental potential is not a result of enhanced TCR-γ gene rearrangement/expression in IL-7R+ pro-T cells. These results indicate that the pro-T cells are heterogeneous in developmental potential before TCR gene rearrangement and suggest that in some precursor cells the initial lineage commitment is independent of TCR-mediated signals.

scholarly journals Gene placement and competition control T cell receptor γ variable region gene rearrangement

2008 ◽  
Vol 205 (4) ◽  
pp. 929-938 ◽  
Author(s):  
Na Xiong ◽  
Li Zhang ◽  
Chulho Kang ◽  
David H. Raulet
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Γδ T Cells ◽  
Variable Region ◽  
Cell Receptor ◽  
Region Gene ◽  
Fetal Thymus ◽  
Thymic Development ◽  
Fetal Stage

The production of distinct sets of T cell receptor (TCR) γδ+ T cells occurs in an ordered fashion in thymic development. The Vγ3 and Vγ4 genes, located downstream in the TCRγ Cγ1 gene cluster, are expressed by the earliest waves of developing TCRγδ+ T cells in the fetal thymus, destined for intraepithelial locations. Upstream Vγ2 and Vγ5 genes are expressed in later waves in the adult and constitute most TCRγδ+ T cells in secondary lymphoid tissue. This developmental pattern is caused in part by a preference for rearrangements of the downstream Vγ3 and Vγ4 genes in the early fetal stage, which switches to a preference for rearrangements of the upstream Vγ2 and Vγ5 gene rearrangements in the adult. Our gene targeting studies show that the downstream Vγ genes rearrange preferentially in the early fetal thymus because of their downstream location, independent of promoter or recombination signal sequences and unrelated to the extent of germline transcription. Remarkably, gene deletion studies show that the downstream Vγ genes competitively inhibit upstream Vγ rearrangements at the fetal stage. These data provide a mechanism for specialization of the fetal thymus for the production of T cells expressing specific Vγ genes.

scholarly journals Splenic γδ T Cells Regulated by CD4+ T Cells Are Required To Control Chronic Plasmodium chabaudi Malaria in the B-Cell-Deficient Mouse

2006 ◽  
Vol 74 (5) ◽  
pp. 2717-2725 ◽  
Author(s):  
Henri C. van der Heyde ◽  
Joan M. Batchelder ◽  
Matyas Sandor ◽  
William P. Weidanz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Blood Stage ◽  
Cell Mediated Immunity ◽  
Γδ T Cell ◽  
Plasmodium Chabaudi ◽  
Antibody Treatment ◽  
Time Courses

ABSTRACT Little is known about the function and regulation of splenic γδ T cells during chronic Plasmodium chabaudi malaria. The splenic γδ T-cell population continues to expand, reaching levels equal to 4 times the number of splenocytes in an uninfected mouse. Splenic γδ T cells from JH −/− mice with chronic malaria expressed Vγ1+ or Vδ4+ in the same ratio as uninfected controls with Vγ1 cells dominating, but the Vγ2 ratio declined about twofold. γδ T cells from G8 mice specific for the TL antigen increased only 2-fold in number, compared with 10-fold in BALB/c controls, but G8 γδ T cells failed to express the B220 activation marker. Elimination of the parasite by drug treatment caused a slow depletion in the number of splenic γδ, CD4+, and CD8+ T cells. Following challenge, drug-cured JH −/− mice exhibited nearly identical parasitemia time courses as naïve controls. Depletion of either CD4+ T cells or γδ T cells from chronically infected JH −/− mice by monoclonal antibody treatment resulted in an immediate and significant (P < 0.05) exacerbation of parasitemia coupled with a marked decrease in splenic γδ T-cell numbers. The number of CD4+ T cells, in contrast, did not decrease in mice after anti-T-cell receptor γδ treatment. The results indicate that cell-mediated immunity against blood-stage malarial parasites during chronic malaria (i) requires the continued presence of blood-stage parasites to remain functional, (ii) is dependent upon both γδ T cells and CD4+ T cells, and (iii) lacks immunological memory.

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