Functional commitment to helper T cell lineage precedes positive selection and is independent of T cell receptor MHC specificity

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.

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A Kinetic Threshold between Negative and Positive Selection Based on the Longevity of the T Cell Receptor–Ligand Complex

Journal of Experimental Medicine ◽

10.1084/jem.189.10.1531 ◽

1999 ◽

Vol 189 (10) ◽

pp. 1531-1544 ◽

Cited By ~ 92

Author(s):

Calvin B. Williams ◽

Deborah L. Engle ◽

Gilbert J. Kersh ◽

J. Michael White ◽

Paul M. Allen

Keyword(s):

T Cells ◽

T Cell ◽

Positive Selection ◽

T Cell Receptor ◽

Cell Receptor ◽

Ligand Complex ◽

Altered Peptide Ligands ◽

Self Peptides ◽

Selection Of

We have developed a unique in vivo system to determine the relationship between endogenous altered peptide ligands and the development of major histocompatibility complex class II– restricted T cells. Our studies use the 3.L2 T cell receptor (TCR) transgenic mouse, in which T cells are specific for Hb(64–76)/I-Ek and positively selected on I-Ek plus self-peptides. To this endogenous peptide repertoire, we have individually added one of six well-characterized 3.L2 ligands. This transgenic approach expands rather than constrains the repertoire of self-peptides. We find that a broad range of ligands produce negative selection of thymocytes in vivo. When compared with the in vitro TCR–ligand binding kinetics, we find that these negatively selecting ligands all have a half-life of 2 s or greater. Additionally, one of two ligands examined with no detectable binding to the 3.L2 TCR and no activity on mature 3.L2 T cells (Q72) enhances the positive selection of transgenic thymocytes in vivo. Together, these data establish a kinetic threshold between negative and positive selection based on the longevity of TCR–ligand complexes.

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

Blood ◽

10.1182/blood.v78.12.3232.3232 ◽

1991 ◽

Vol 78 (12) ◽

pp. 3232-3240 ◽

Cited By ~ 8

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.

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

Journal of Experimental Medicine ◽

10.1084/jem.190.9.1257 ◽

1999 ◽

Vol 190 (9) ◽

pp. 1257-1262 ◽

Cited By ~ 1

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.

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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 ◽

10.1182/blood.v75.9.1834.1834 ◽

1990 ◽

Vol 75 (9) ◽

pp. 1834-1840 ◽

Cited By ~ 56

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.

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T-cell receptor delta/alpha rearrangements in lymphoid neoplasms

Blood ◽

10.1182/blood.v74.3.1073.1073 ◽

1989 ◽

Vol 74 (3) ◽

pp. 1073-1083 ◽

Cited By ~ 37

Author(s):

MJ Dyer

Keyword(s):

T Cell ◽

B Cell ◽

T Cell Receptor ◽

Cell Lineage ◽

Cell Receptor ◽

Lymphocytic Leukemia ◽

Cell Precursor ◽

Lymphoid Neoplasms ◽

Histiocytic Lymphoma ◽

T Cell Malignancies

Abstract Rearrangements within the T-cell receptor (TCR)delta/alpha locus were analyzed in a wide variety of lymphoid neoplasms by eight DNA probes specific for TCR J delta, J alpha and C alpha segments. In all 11 T- cell malignancies, rearrangement and/or deletion of TCR delta was detected irrespective of the stage of maturation of the tumor. The organization of TCR delta correlated with the phenotype of the tumor: In “prethymic” T-cell acute lymphocytic leukemia (ALL), TCR delta was the only TCR gene to be rearranged. More mature T cell malignancies expressing CD4 together with CD3 showed deletion of both alleles of TCR delta, suggestive of TCR V alpha-J alpha rearrangement. All 43 B-cell tumors expressing surface immunoglobulin (sIg), including two cases of adult B-cell ALL, had germline configuration of TCR delta/alpha. In contrast, all 17 B-cell precursor ALLs (null, common, and pre-B-cell ALLs) had rearrangement and/or deletion of TCR delta/alpha. A single case of “histiocytic” lymphoma also showed biallelic deletion of TCR delta. Oligoclonal rearrangements of Ig and TCR genes were observed in two cases of B-cell precursor ALL and in one case of T-cell lymphoblastic lymphoma. Patterns of such “aberrant” TCR rearrangement were similar to those observed in T-lineage malignancies. In particular, seven of eight cases of B-cell precursor ALL and the histiocytic lymphoma which demonstrated biallelic TCR delta deletion, (suggestive of a V alpha-J alpha rearrangement) had clonal TCR beta rearrangement. These data support the hypothesis that supposedly aberrant rearrangements of the TCR genes may follow the same developmental controls as found in T-cell differentiation, despite the lack of evidence for further commitment to the T-cell lineage. TCR delta rearrangement is a useful marker of clonality of immature T-cell tumors which may have only this gene rearranged but is not specific to the T-cell lineage.

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Distinct phases in the positive selection of CD8+ T cells distinguished by intrathymic migration and T-cell receptor signaling patterns

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1408482111 ◽

2014 ◽

Vol 111 (25) ◽

pp. E2550-E2558 ◽

Cited By ~ 30

Author(s):

J. O. Ross ◽

H. J. Melichar ◽

B. B. Au-Yeung ◽

P. Herzmark ◽

A. Weiss ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Positive Selection ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Cell Receptor ◽

Receptor Signaling ◽

T Cell Receptor Signaling ◽

Cell Receptor Signaling ◽

Selection Of

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Interleukin 3 (IL-3) induces transcription from nonrearranged T cell receptor gamma loci in IL-3-dependent cell lines.

Journal of Experimental Medicine ◽

10.1084/jem.169.6.2059 ◽

1989 ◽

Vol 169 (6) ◽

pp. 2059-2071 ◽

Cited By ~ 20

Author(s):

Y Weinstein ◽

K Morishita ◽

J L Cleveland ◽

J N Ihle

Keyword(s):

T Cell ◽

Growth Factor ◽

T Cell Receptor ◽

Cell Lines ◽

Cell Lineage ◽

Cell Receptor ◽

Cdna Clones ◽

Gene Rearrangements ◽

Interleukin 3 ◽

Dependent Cell

The expression of the murine TCR-gamma genes was examined in a series of IL-3-dependent and growth factor-independent cell lines. All of the IL-3-dependent cell lines, but none of the IL-3-independent lines, expressed high levels of one or more of the gamma genes but did not express the TCR-beta genes. None of the cell lines expressing the gamma loci contained detectable genomic gamma gene rearrangements. Sequencing of cDNA clones from two of the cell lines demonstrated that transcription was from nonrearranged gamma loci based on the presence of sequences in the cDNAs that are found immediately 5' of the J gamma 4 and J gamma 2 genes. The expression of gamma transcripts was dependent upon IL-3 and no transcripts were detectable within 6-8 h after the removal of IL-3. Readdition of IL-3, but not granulocyte CSF, resulted in the reappearance of gamma transcripts within 30 min. The results demonstrate that IL-3 regulates the expression of nonrearranged gamma loci. Since expression is required for rearrangement, it can be hypothesized that IL-3 may influence the ability of lymphoid/myeloid progenitors to commit to the T cell lineage.

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