scholarly journals Involvement of the interleukin 2 pathway in the rearrangement and expression of both alpha/beta and gamma/delta T cell receptor genes in human T cell precursors.

1988 ◽  
Vol 168 (6) ◽  
pp. 2231-2249 ◽  
Author(s):  
M L Toribio ◽  
A de la Hera ◽  
J Borst ◽  
M A Marcos ◽  
C Márquez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Beta Chain ◽  
Gamma Delta ◽  
Human T Cell ◽  
Alpha Beta ◽  
A Minor

In this report, we have undertaken the phenotypic, functional and molecular characterization of a minor (less than 5%) subpopulation of adult thymocytes regarded as the earliest intrathymic T-cell precursors. Pro-T cells were immunoselected and shown to express different hematopoietic cell markers (CD45, CD38, CD7, CD5) and some activation-related molecules (4F2, Tr, HLA class II), but lack conventional T cell antigens (CD2-1-3-4-8-). TCR-gamma RNA messages are already expressed at this early ontogenic stage, while alpha and beta chain TCR genes remain in germline configuration. In vitro analyses of the growth requirements of pro-T cells demonstrated the involvement of the IL-2 pathway in promoting their proliferation and differentiation into CD3+ CD4+ or CD8+ mature thymocytes. Moreover, during the IL-2-mediated maturation process rearrangements and expression of both alpha and beta chain TCR genes occurred, and resulted in the acquisition of alpha/beta as well as gamma/delta (either disulphide-linked or non-disulphide-linked) heterodimeric TCR among the pro-T cell progeny.

scholarly journals Thalidomide Costimulates Primary Human T Lymphocytes, Preferentially Inducing Proliferation, Cytokine Production, and Cytotoxic Responses in the CD8+ Subset

1998 ◽  
Vol 187 (11) ◽  
pp. 1885-1892 ◽  
Author(s):  
Patrick A.J. Haslett ◽  
Laura G. Corral ◽  
Matthew Albert ◽  
Gilla Kaplan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Cell Subset ◽  
Cell Receptor ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
T Cell Subset ◽  
Human T Cell

The efficacy of thalidomide (α-phthalimido-glutarimide) therapy in leprosy patients with erythema nodosum leprosum is thought to be due to inhibition of tumor necrosis factor α. In other diseases reported to respond to thalidomide, the mechanism of action of the drug is unclear. We show that thalidomide is a potent costimulator of primary human T cells in vitro, synergizing with stimulation via the T cell receptor complex to increase interleukin 2–mediated T cell proliferation and interferon γ production. The costimulatory effect is greater on the CD8+ than the CD4+ T cell subset. The drug also increases the primary CD8+ cytotoxic T cell response induced by allogeneic dendritic cells in the absence of CD4+ T cells. Therefore, human T cell costimulation can be achieved pharmacologically with thalidomide, and preferentially in the CD8+ T cell subset.

scholarly journals T cell receptor ligation induces interleukin (IL) 2R beta chain expression in rat CD4,8 double positive thymocytes, initiating an IL-2-dependent differentiation pathway of CD8 alpha+/beta- T cells.

1993 ◽  
Vol 177 (2) ◽  
pp. 541-546 ◽  
Author(s):  
J H Park ◽  
R Mitnacht ◽  
N Torres-Nagel ◽  
T Hünig
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cell Receptor ◽  
Beta Chain ◽  
Double Positive ◽  
Alpha Chain ◽  
Alpha Beta

The role of interleukin (IL)2 in intrathymic T cell development is highly controversial, and nothing is known about IL-2R expression on thymocytes of the T cell receptor (TCR) alpha/beta lineage undergoing TCR-driven differentiation events. We analyze here IL-2R alpha and beta mRNA expression in an in vitro system where newly generated rat CD4,8 double positive (DP) thymocytes respond to TCR ligation plus IL-2 (but not to either stimulus alone) with rapid differentiation to functional CD8 single positive T cells (Hünig, T., and R. Mitnacht. 1991. J. Exp. Med. 173:561). TCR ligation induced expression of IL-2R beta (but not alpha) chain mRNA in DP thymocytes. Addition of IL-2 then lead to functional maturation and expression of the IL-2R alpha chain. To investigate if the CD8 T cells generated via this IL-2R beta-driven pathway in vitro correspond to the bulk of CD8 T cells seeding peripheral lymphoid organs in vivo, we compared their phenotype to that of lymph node CD8 T cells. Surprisingly, analysis of CD8 cell surface expression using a novel anti-CD8 monoclonal antibody specific for the alpha/beta heterodimeric isoform, and of CD8 alpha and beta chain mRNA revealed that T cells generated by TCR ligation plus IL-2 resemble thymus-independent rather than thymus-derived CD8 cells in that they express CD8 alpha without beta chains. These findings demonstrate that TCR crosslinking induces functional IL-2R on immature DP rat thymocytes. In addition, they show that at least in vitro, CD8 alpha/alpha T cells are generated from TCR-stimulated DP thymocytes (which express the CD8 alpha/beta in the heterodimeric isoform) along an IL-2-driven pathway of T cell differentiation.

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 Germinal center formation, immunoglobulin class switching, and autoantibody production driven by "non alpha/beta" T cells.

1996 ◽  
Vol 183 (5) ◽  
pp. 2271-2282 ◽  
Author(s):  
L Wen ◽  
W Pao ◽  
F S Wong ◽  
Q Peng ◽  
J Craft ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lupus Erythematosus ◽  
Cell Receptor ◽  
Gamma Delta T Cells ◽  
Gamma Delta ◽  
Autoantibody Production ◽  
Ige Synthesis ◽  
Alpha Beta ◽  
T Cell Help

The production of class-switched antibodies, particularly immunoglobulin (Ig) G1 and IgE, occurs efficiently in T cell receptor (TCR) alpha-/- mice that are congenitally devoid of alpha/beta T cells. This finding runs counter to a wealth of data indicating that IgG1 and IgE synthesis are largely dependent on the collaboration between B and alpha/beta T cells. Furthermore, many of the antibodies synthesized in TCR alpha-/- mice are reactive to a similar spectrum of self-antigens as that targeted by autoantibodies characterizing human systemic lupus erythematosus (SLE). SLE, too, is most commonly regarded as an alpha/beta T cell-mediated condition. To distinguish whether the development of autoantibodies in TCR alpha-/- mice is due to an intrinsic de-regulation of B cells, or to a heretofore poorly characterized collaboration between B and "non-alpha/beta T" cells, the phenotype has been reconstituted by transfer of various populations of B and non-alpha/beta T cells including cloned gamma/delta T cells derived from TCR alpha-/- mice, to severe combined immunodeficient (SCID) mice. The results establish that the reproducible production of IgG1 (including autoantibodies) is a product of non-alpha/beta T cell help that can be provided by gamma/delta T cells. This type of B-T collaboration sustains the production of germinal centers, lymphoid follicles that ordinarily are anatomical signatures of alpha/beta T-B cell collaboration. Thus, non-alpha/beta T cell help may drive Ig synthesis and autoreactivity under various circumstances, especially in cases of alpha/beta T cell immunodeficiency.

scholarly journals A delta T-cell receptor deleting element transgenic reporter construct is rearranged in alpha beta but not gamma delta T-cell lineages.

1995 ◽  
Vol 15 (12) ◽  
pp. 7022-7031 ◽  
Author(s):  
J Shutter ◽  
J A Cain ◽  
S Ledbetter ◽  
M D Rogers ◽  
R D Hockett
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Receptor ◽  
Chain Gene ◽  
Gamma Delta ◽  
Alpha Chain ◽  
Chain Locus ◽  
Discrete Population ◽  
Alpha Beta ◽  
Gamma Delta T Cell

T cells can be divided into two groups on the basis of the expression of either alpha beta or gamma delta T-cell receptors (TCRs). Because the TCR delta chain locus lies within the larger TCR alpha chain locus, control of the utilization of these two receptors is important in T-cell development, specifically for determination of T-cell type: rearrangement of the alpha locus results in deletion of the delta coding segments and commitment to the alpha beta lineage. In the developing thymus, a relative site-specific recombination occurs by which the TCR delta chain gene segments are deleted. This deletion removes all D delta, J delta, and C delta genes and occurs on both alleles. This delta deletional mechanism is evolutionarily conserved between mice and humans. Transgenic mice which contain the human delta deleting elements and as much internal TCR delta chain coding sequence as possible without allowing the formation of a complete delta chain gene were developed. Several transgenic lines showing recombinations between deleting elements within the transgene were developed. These lines demonstrate that utilization of the delta deleting elements occurs in alpha beta T cells of the spleen and thymus. These recombinations are rare in the gamma delta population, indicating that the machinery for utilization of delta deleting elements is functional in alpha beta T cells but absent in gamma delta T cells. Furthermore, a discrete population of early thymocytes containing delta deleting element recombinations but not V alpha-to-J alpha rearrangements has been identified. These data are consistent with a model in which delta deletion contributes to the implementation of a signal by which the TCR alpha chain locus is rearranged and expressed and thus becomes an alpha beta T cell.

scholarly journals Evidence for in vivo clonal proliferation of unique population of blood CD4-/CD8- T cells bearing T-cell receptor alpha and beta chains in two normal men

Blood ◽  
1992 ◽  
Vol 79 (11) ◽  
pp. 2965-2972 ◽  
Author(s):  
Y Kusunoki ◽  
Y Hirai ◽  
S Kyoizumi ◽  
M Akiyama
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Nk Cell ◽  
Cell Receptor ◽  
Cell Markers ◽  
Clonal Proliferation ◽  
Alpha Beta

Abstract Rare T lymphocytes bearing CD3 surface antigen and T-cell receptor (TCR) alpha and beta chains, but lacking both CD4 and CD8 antigens, viz, TCR alpha beta+CD4–8- cells, appear at a frequency of 0.1% to 2% in peripheral blood TCR alpha beta+ cells of normal donors. Here we report two unusual cases, found among 100 healthy individuals studied, who showed an abnormally elevated frequency of these T cells, ie, 5% to 10% and 14% to 19%. Southern blot analyses of the TCR alpha beta+CD4–8- clones all showed the identical rearrangement patterns for each individual, demonstrating that these are derivatives of a single T cell. The same rearrangement patterns were also observed for the freshly isolated lymphocytes of TCR alpha beta+CD4-CD8- fraction, which excludes the possible bias in the processes of in vitro cloning. These TCR alpha beta+CD4–8- T cells were found to express other mature T-cell markers such as CD2, CD3, and CD5 antigens, as well as natural killer (NK) cell markers (CD11b, CD16, CD56, and CD57 antigens) for both individuals. Further, although lectin-dependent or redirected antibody- dependent cell-mediated cytotoxicities were observed for both freshly sorted lymphocytes of TCR alpha beta+CD4–8- fraction and in vitro established clones, NK-like activity was not detected.

β-Selection Is Associated With the Onset of CD8β Chain Expression on CD4+CD8+ Pre-T Cells During Human Intrathymic Development

Blood ◽  
1999 ◽  
Vol 94 (10) ◽  
pp. 3491-3498 ◽  
Author(s):  
Yolanda R. Carrasco ◽  
César Trigueros ◽  
Almudena R. Ramiro ◽  
Virginia G. de Yébenes ◽  
Marı́a L. Toribio
Keyword(s):  
T Cells ◽  
T Cell ◽  
Control Point ◽  
Intermediate Stage ◽  
Cell Receptor ◽  
Resting Cells ◽  
Double Positive ◽  
Human T Cell ◽  
A Minor

T-cell precursors that undergo productive rearrangements at the T-cell receptor (TCR) β locus are selected for proliferation and further maturation, before TCR expression, by signaling through a pre–TCR composed of the TCRβ chain paired with a pre–TCR (pT) chain. Such a critical developmental checkpoint, known as β-selection, results in progression from CD4−CD8− double negative (DN) to CD4+CD8+ double positive (DP) TCRβ−thymocytes. In contrast to mice, progression to the DP compartment occurs in humans via a CD4+ CD8−intermediate stage. Here we show that the CD4+CD8− to CD4+ CD8+ transition involves the sequential acquisition of the  and β chains of CD8 at distinct maturation stages. Our results indicate that CD8, but not CD8β, is expressed in vivo in a minor subset of DP TCRβ− thymocytes, referred to as CD4+CD8+ pre-T cells, mostly composed of resting cells lacking cytoplasmic TCRβ chain (TCRβic). In contrast, expression of CD8β heterodimers was selectively found on DP TCRβ− thymocytes that express TCRβicand are enriched for cycling cells. Interestingly, CD4+CD8+ pre-T cells are shown to be functional intermediates between CD4+ CD8−TCRβic− and CD4+CD8β+ TCRβic+thymocytes. More importantly, evidence is provided that onset of CD8β and TCRβic expression are coincident developmental events associated with acquisition of CD3 and pT chain on the cell surface. Therefore, we propose that the CD4+CD8+ to CD4+CD8β+ transition marks the key control point of pre-TCR–mediated β-selection in human T-cell development.

scholarly journals A gamma/delta cell receptor heterodimer induces the expression of CD4 and CD8 in thymocytes.

1991 ◽  
Vol 174 (1) ◽  
pp. 293-296 ◽  
Author(s):  
M Iwashima ◽  
M M Davis ◽  
Y H Chien
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Receptor ◽  
Surface Expression ◽  
Gamma Delta T Cells ◽  
Gamma Delta ◽  
Double Positive ◽  
Continuous Surface ◽  
Delta Cell ◽  
Alpha Beta

CD4 and CD8 have been useful surface markers for alpha/beta T cell maturation. In an alpha/beta T cell receptor (TCR) transgenic SCID mice system, it has been shown that alpha/beta TCR alone is sufficient to induce CD4 and CD8 surface expression on thymic T cells. Although the late embryonic thymic gamma/delta T cells are predominately single and double positive, it has not been clear if gamma/delta TCR has a similar capacity. In this study, we show that when transgenes encoding the earliest embryonic gamma/delta TCR are coexpressed with the SCID defect, the gamma/delta transgenes promote the appearance of both the CD4-8- and CD4+8+ T cells in the thymus. Furthermore, the expression of CD4 and CD8 does not require continuous surface gamma/delta TCR expression. These results indicate that gamma/delta TCR alone can promote the CD4/8 surface expression, and may suggest a role for gamma/delta T cells in initiating normal thymic ontogeny.

scholarly journals Surface expression of functional T cell receptor chains formed by interlocus recombination on human T lymphocytes.

1994 ◽  
Vol 180 (5) ◽  
pp. 1685-1691 ◽  
Author(s):  
F Davodeau ◽  
M A Peyrat ◽  
J Gaschet ◽  
M M Hallet ◽  
F Triebel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Surface Expression ◽  
Structural Features ◽  
Gamma Delta ◽  
Cell Repertoire ◽  
Repertoire Selection ◽  
Alpha Beta

Structural diversity of lymphocyte antigen receptors (the immunoglobulin [Ig] of B cells and the alpha/beta or gamma/delta T cell receptor [TCR] of T cells) is generated through somatic rearrangements of V, D, and J gene segments. Classically, these recombination events involve gene segments from the same Ig or TCR locus. However, occurrence of "trans" rearrangements between distinct loci has also been described, although in no instances was the surface expression of the corresponding protein under normal physiological conditions demonstrated. Here we show that hybrid TCR genes generated by trans rearrangement between V gamma and (D) J beta elements are translated into functional antigen receptor chains, paired with TCR alpha chains. Like classical alpha/beta T cells, cells expressing these hybrid TCR chains express either CD4 or CD8 coreceptors and are frequently alloreactive. These results have several implications in terms of T cell repertoire selection and relationships between TCR structure and specificity. First, they suggest that TCR alloreactivity is determined by the repertoire selection processes operating during lymphocyte development rather than by structural features specific to V alpha V beta regions. Second, they suggest the existence of close structural relationships between gamma/delta and alpha/beta TCR and more particularly, between V gamma and V beta regions. Finally, since a significant fraction of PBL (at least 1/10(4)) expressed hybrid TCR chains on their surface, these observations indicate that trans rearrangements significantly contribute to the combinatorial diversification of the peripheral immune repertoire.

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