The molecular assembly of the marsupial γμ T cell receptor defines a third T cell lineage

Science ◽  
2021 ◽  
Vol 371 (6536) ◽  
pp. 1383-1388 ◽  
Author(s):  
Kimberly A. Morrissey ◽  
Marcin Wegrecki ◽  
T. Praveena ◽  
Victoria L. Hansen ◽  
Lijing Bu ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Molecular Assembly ◽  
Structural Basis ◽  
Antigen Receptors ◽  
Single Domain Antibody ◽  
Cell Lineages ◽  
Evolutionarily Conserved ◽  
Major Antigen

αβ and γδ T cell receptors (TCRs) are highly diverse antigen receptors that define two evolutionarily conserved T cell lineages. We describe a population of γμTCRs found exclusively in non-eutherian mammals that consist of a two-domain (Vγ-Cγ) γ-chain paired to a three-domain (Vμ-Vμj-Cμ) μ-chain. γμTCRs were characterized by restricted diversity in the Vγ and Vμj domains and a highly diverse unpaired Vμ domain. Crystal structures of two distinct γμTCRs revealed the structural basis of the association of the γμTCR heterodimer. The Vμ domain shared the characteristics of a single-domain antibody within which the hypervariable CDR3μ loop suggests a major antigen recognition determinant. We define here the molecular basis underpinning the assembly of a third TCR lineage, the γμTCR.

Ig alpha and Ig beta are functionally homologous to the signaling proteins of the T-cell receptor

1994 ◽  
Vol 14 (2) ◽  
pp. 1095-1103
Author(s):  
A L Burkhardt ◽  
T Costa ◽  
Z Misulovin ◽  
B Stealy ◽  
J B Bolen ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Receptor ◽  
Interleukin 2 ◽  
Antigen Receptor ◽  
Cell Receptor ◽  
Antigen Receptors ◽  
Cell Antigen

Signal transduction by antigen receptors and some Fc receptors requires the activation of a family of receptor-associated transmembrane accessory proteins. One common feature of the cytoplasmic domains of these accessory molecules is the presence is at least two YXXA repeats that are potential sites for interaction with Src homology 2 domain-containing proteins. However, the degree of similarity between the different receptor-associated proteins varies from that of T-cell receptor (TCR) zeta and Fc receptor RIIIA gamma chains, which are homologous, to the distantly related Ig alpha and Ig beta proteins of the B-cell antigen receptor. To determine whether T- and B-cell antigen receptors are in fact functionally homologous, we have studied signal transduction by chimeric immunoglobulins bearing the Ig alpha or Ig beta cytoplasmic domain. We found that Ig alpha and Ig beta cytoplasmic domains were able to activate Ca2+ flux, interleukin-2 secretion, and phosphorylation of the same group of cellular substrates as the TCR in transfected T cells. Chimeric proteins were then used to examine the minimal requirements for activation of the Fyn, Lck, and ZAP kinases in T cells. Both Ig alpha and Ig beta were able to trigger Fyn, Lck, and ZAP directly without involvement of TCR components. Cytoplasmic tyrosine residues in Ig beta were required for recruitment and activation of ZAP-70, but these amino acids were not essential for the activation of Fyn and Lck. We conclude that Fyn and Lck are able to recognize a clustered nonphosphorylated immune recognition receptor, but activation of these kinases is not sufficient to induce cellular responses such as Ca2+ flux and interleukin-2 secretion. In addition, the molecular structures involved in antigen receptor signaling pathways are conserved between T and B cells.

scholarly journals Commitment of Common T/Natural Killer (Nk) Progenitors to Unipotent T and Nk Progenitors in the Murine Fetal Thymus Revealed by a Single Progenitor Assay

1999 ◽  
Vol 190 (11) ◽  
pp. 1617-1626 ◽  
Author(s):  
Tomokatsu Ikawa ◽  
Hiroshi Kawamoto ◽  
Shinji Fujimoto ◽  
Yoshimoto Katsura
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
T Cell Receptor ◽  
Cell Lineage ◽  
Cell Receptor ◽  
The Other ◽  
Fetal Thymus ◽  
Β Chain ◽  
Clonal Assay

We have established a new clonal assay system that can evenly support the development of T and natural killer (NK) cells. With this system, we show that all T cell progenitors in the earliest CD44+CD25−FcγRII/III− fetal thymus (FT) cell population retain NK potential, and that the NK lineage–committed progenitors (p-NK) also exist in this population. T cell lineage–committed progenitors (p-T), which are unable to generate NK cells, first appear at the CD44+CD25− FcγRII/III+ stage in day 12 FT. The proportion of p-T markedly increases during the transition from the CD44+CD25− stage to the CD44+CD25+ stage in day 14 FT. On the other hand, p-NK preferentially increase in number at the CD44+CD25− stage between days 12 and 14 of gestation. The production of p-NK continues up to the CD44+CD25+ stage, but ceases before the rearrangement of T cell receptor β chain genes. It was further shown that the CD44+CD25− CD122+ population of day 14 FT exclusively contains p-NK. These results indicate that the earliest T cell progenitor migrating into the FT is T/NK bipotent, and strongly suggest that the bipotent progenitor continuously produces p-NK and p-T until the CD44+CD25+ stage.

scholarly journals Activation via the CD3 and CD16 pathway mediates interleukin-2- dependent autocrine proliferation of granular lymphocytes in patients with granular lymphocyte proliferative disorders

Blood ◽  
1991 ◽  
Vol 78 (12) ◽  
pp. 3232-3240 ◽  
Author(s):  
S Hoshino ◽  
K Oshimi ◽  
M Teramura ◽  
H Mizoguchi
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Cell Phenotype ◽  
Beta Chain ◽  
Alpha Beta ◽  
Granular Lymphocytes

Abstract Granular lymphocytes (GLs) in patients with GL-proliferative disorders (GLPDs) are known to express the interleukin-2 receptor (IL-2R) beta chain (p70–75) constitutively and to proliferate in response to stimulation with IL-2 via the beta chain. In this report, we found that the anti-CD3 monoclonal antibody (MoAb) OKT3 could induce the proliferation of GLs from patients with T-cell lineage GLPDs (T-cell receptor-alpha beta+/CD3+16+), but not that of natural killer (NK) cell lineage GLs (T-cell receptor-alpha beta-/CD3–16+). In contrast, the anti-CD16 MoAb 3G8 that reacts with NK-lineage GLs could induce the proliferation of these GLs but not that of GLs with a T-cell phenotype. Furthermore, the anti-CD16 MoAbs CLB FcR gran1 (VD2) and OK-NK, which react with both T- and NK-lineage GLs, induced the proliferation of GLs with both T- and and NK-cell phenotypes. The proliferative response induced via the CD3 or IgG Fc receptor III (Fc gamma RIII: CD16) pathway was shown to be associated with the IL-2-dependent autocrine pathway by various findings, including the induction of endogenous IL-2 production, the coexpression of the IL-2R alpha chain (p55) and the IL- 2R beta chain, and the inhibition of GL proliferation by anti-IL-2 or anti-IL-2R MoAb. These results suggest that GL proliferation is mediated at least partly through the IL-2-dependent autocrine pathway, and that the TCR/CD3 complex in T-cell phenotype GLs and the Fc gamma RIII in both T- and NK-cell phenotype GLs play a role in their activation in GLPDs.

scholarly journals Irradiation-Mediated Rescue of T Cell–Specific V(D)j Recombination and Thymocyte Differentiation in Severe Combined Immunodeficient Mice by Bone Marrow Cells

1999 ◽  
Vol 190 (9) ◽  
pp. 1257-1262 ◽  
Author(s):  
Chiyu Wang ◽  
Molly A. Bogue ◽  
Jonathan M. Levitt ◽  
David B. Roth
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
T Cell Receptor ◽  
T Lymphocyte ◽  
Bone Marrow Cells ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Immunodeficient Mice ◽  
Thymocyte Differentiation ◽  
Marrow Cells

In SCID (severe combined immunodeficient) mice, proper assembly of immunoglobulin and T cell receptor (TCR) genes is blocked by defective V(D)J recombination so that B and T lymphocyte differentiation is arrested at an early precursor stage. Treating the mice with gamma irradiation rescues V(D)J rearrangement at multiple TCR loci, promotes limited thymocyte differentiation, and induces thymic lymphomas. These effects are not observed in the B cell lineage. Current models postulate that irradiation affects intrathymic T cell precursors. Surprisingly, we found that transfer of irradiated SCID bone marrow cells to unirradiated host animals rescues both TCR rearrangements and thymocyte differentiation. These data indicate that irradiation affects precursor cells at an earlier stage of differentiation than was previously thought and suggest new models for the mechanism of irradiation rescue.

scholarly journals High prevalence of T-cell receptor V delta 2-(D)-D delta 3 or D delta 1/2-D delta 3 rearrangements in B-precursor acute lymphoblastic leukemias

Blood ◽  
1990 ◽  
Vol 75 (9) ◽  
pp. 1834-1840 ◽  
Author(s):  
A Biondi ◽  
P Francia di Celle ◽  
V Rossi ◽  
G Casorati ◽  
G Matullo ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Lymphoblastic Leukemia ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Lymphoproliferative Disorders ◽  
Cell Precursor ◽  
Gene Assembly ◽  
Lymphoid Malignancies ◽  
High Prevalence

Abstract Rearrangement of the immunoglobulin (Ig) and T-cell receptor (TcR) genes generally has been considered a useful marker of B- and T-cell lineage in lymphoproliferative disorders. However, concomitant rearrangements of Ig and TcR genes have been commonly reported in the most immature lymphoid malignancies, mainly in B-cell precursor acute lymphoblastic leukemia (ALL). To better characterize the nature of this lineage promiscuity, we have analyzed the configuration of the TcR delta locus in 75 B-precursor ALL. The large majority of cases (87%) displayed a rearrangement or deletion at the delta locus. Among the 57 nondeletional rearrangements, two patterns were predominant and both appeared to derive from partial joining: a V delta-(D)-D delta 3 (32/57) and a D delta 1/2-D delta 3 (11/57) type. A single V delta gene (V delta 2) appeared to be involved in the first type of rearrangement. These findings are at variance with T-ALL, where rearrangements 5′ to V delta 2 are usually found. It remains to be elucidated whether this incomplete attempt of V delta 2 gene assembly is related to the neoplastic event or represents a physiologic predisposition occurring during early stages of the normal lymphocyte differentiation.

scholarly journals Defined αβ T Cell Receptors with Distinct Ligand Specificities Do Not Require Those Ligands to Signal Double Negative Thymocyte Differentiation

2004 ◽  
Vol 199 (12) ◽  
pp. 1719-1724 ◽  
Author(s):  
Batu Erman ◽  
Terry I. Guinter ◽  
Alfred Singer
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Receptor ◽  
Peptide Ligands ◽  
Double Negative ◽  
Antigen Receptors ◽  
Double Positive ◽  
Recombination Activating Gene ◽  
Thymocyte Differentiation ◽  
Deficient Mice

During T cell development in the thymus, pre–T cell receptor (TCR) complexes signal CD4− CD8− (double negative [DN]) thymocytes to differentiate into CD4+ CD8+ (double positive [DP]) thymocytes, and they generate such signals without apparent ligand engagements. Although ligand-independent signaling is unusual and might be unique to the pre-TCR, it is possible that other TCR complexes such as αβ TCR or αγ TCR might also be able to signal the DN to DP transition in the absence of ligand engagement if they were expressed on DN thymocytes. Although αγ TCR complexes efficiently signal DN thymocyte differentiation, it is not yet certain if αβ TCR complexes are also capable of signaling DN thymocyte differentiation, nor is it certain if such signaling is dependent upon ligand engagement. This study has addressed these questions by expressing defined αβ TCR transgenes in recombination activating gene 2−/− pre-Tα−/− double deficient mice. In such double deficient mice, the only antigen receptors that can be expressed are those encoded by the αβ TCR transgenes. In this way, this study definitively demonstrates that αβ TCR can in fact signal the DN to DP transition. In addition, this study demonstrates that transgenic αβ TCRs signal the DN to DP transition even in the absence of their specific MHC–peptide ligands.

scholarly journals SOX4 controls invariant NKT cell differentiation by tuning TCR signaling

2018 ◽  
Vol 215 (11) ◽  
pp. 2887-2900 ◽  
Author(s):  
Nidhi Malhotra ◽  
Yilin Qi ◽  
Nicholas A. Spidale ◽  
Michela Frascoli ◽  
Bing Miu ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lineage ◽  
High Mobility ◽  
Allergic Diseases ◽  
Cell Receptor ◽  
Inkt Cells ◽  
Tcr Signaling ◽  
Nkt Cell ◽  
Essential Function ◽  
Lineage Diversification

Natural killer T (NKT) cells expressing the invariant T cell receptor (iTCR) serve an essential function in clearance of certain pathogens and have been implicated in autoimmune and allergic diseases. Complex effector programs of these iNKT cells are wired in the thymus, and upon thymic egress, they can respond within hours of antigenic challenges, classifying iNKT cells as innate-like. It has been assumed that the successful rearrangement of the invariant iTCRα chain is the central event in the divergence of immature thymocytes to the NKT cell lineage, but molecular properties that render the iTCR signaling distinct to permit the T cell lineage diversification remain obscure. Here we show that the High Mobility Group (HMG) transcription factor (TF) SOX4 controls the production of iNKT cells by inducing MicroRNA-181 (Mir181) to enhance TCR signaling and Ca2+ fluxes in precursors. These results suggest the existence of tailored, permissive gene circuits in iNKT precursors for innate-like T cell development.

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