Differentiation of human mature thymocytes: Existence of a T3+4−8− intermediate stage

Hera, Alberto De La; Toribio, Marı́a L.; Márquez, Carlos; Marcos, Miguel A. R.; Cabrero, Esther; Martı́nez-A, Carlos

doi:10.1002/eji.1830160611

Cited by 29 publications

(27 citation statements)

References 41 publications

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“…Indeed, a mutation in the extracellular domain of CD95L has been reported in a patient diagnosed as having atypical lupus erythematosus. 23 In humans, TCR-␣␤ DN T cells are normally found in the thymus, 24 skin, 25 and peripheral blood. 25,26 They represent a small subpopulation of peripheral blood lymphocytes in most healthy adults but are increased in some patients with systemic and cutaneous autoimmune disorders.…”

Section: Discussionmentioning

confidence: 99%

Pathological Findings in Human Autoimmune Lymphoproliferative Syndrome

Lim¹,

Straus²,

Dale³

et al. 1998

The American Journal of Pathology

211

127

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The defects in lymphocyte apoptosis that underlie the autoimmune lymphoproliferative syndrome (ALPS) are usually attributable to inherited mutations of the CD95 (Fas) gene. In this report , we present the histopathological and immunophenotypic features seen in the lymph nodes (n ‫؍‬ 16) , peripheral blood (n ‫؍‬ 10) , bone marrow (n ‫؍‬ 2) , spleen (n ‫؍‬ 3) , and liver (n ‫؍‬ 2) from 10 patients with ALPS. Lymph nodes showed marked paracortical hyperplasia. Interfollicular areas were expanded and populated by T cell receptor-␣␤ CD3 ؉ CD4 ؊ CD8 ؊ (double-negative, DN) T cells that were negative for CD45RO. CD45RA؉ T cells were increased in all cases studied. The paracortical infiltrate was a result of both reduced apoptosis and increased proliferation , as measured by in situ detection of DNA fragmentation and staining with MIB-1 , respectively. The paracortical proliferation may be extensive enough to suggest a diagnosis of malignant lymphoma. Many of the paracortical lymphocytes expressed markers associated with cytotoxicity , such as perforin , TIA-1 , and CD57. CD25 was negative. In addition , most lymph nodes exhibited florid follicular hyperplasia , often with focal progressive transformation of germinal centers; in some cases , follicular involution was seen. A polyclonal plasmacytosis also was present. The spleens were markedly enlarged , more than 10 times normal size. There was expansion of both white pulp and red pulp , with increased DN T cells. DN T cells also were observed in liver biopsies exhibiting portal triaditis. In the peripheral blood , the T cells showed increased expression of HLA-DR and CD57 but not CD25. CD45RA؉ T cells were increased in the four cases CD8Ϫ , doublenegative (DN) T cells in the circulation and lymphoid tissues. Sneller et al 1 first reported a detailed clinical and immunological study of two patients, recognizing similarities to the MRL and C3H/Hej strains of mice possessing the lpr and gld mutations, respectively. Genetic elucidation of the lpr and gld loci as representing recessive mutations in the genes encoding CD95 (Fas/Apo-1) and CD95L (FasL), respectively, 2-4 led to the discovery of functional CD95 mutations in ALPS patients. [5][6][7][8] With the ability to diagnose specific CD95 mutations in ALPS cases, it was appreciated that patients affected with this disorder had been included in published series by a number of investigators of undefined chronic lymphoproliferation or splenomegaly with associated autoimmune phenomena. 9,10

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Section: Discussionmentioning

confidence: 99%

Pathological Findings in Human Autoimmune Lymphoproliferative Syndrome

Lim¹,

Straus²,

Dale³

et al. 1998

The American Journal of Pathology

211

127

View full text Add to dashboard Cite

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“…Most CD1 + double-positive thymocytes generated in vitro bear cytoplasmic TCR/3 chain, indicating that they are a/3 pre-T cells, and some may express low levels of TCR -CD3 on the cell membrane. CD1 + TCR-CD3+ thymocytes cannot be expanded in vitro, nor can normal peripheral mature CD1 + T cells be detected ex vivo (Table 1; unpublished observations). Interestingly enough, a minor subset (<5%) of CD1-3 + double-positives occurs in vivo We have previously shown that polyclonal activators such as PHA and IL2 stimulate the generation of such CD1-3+ double-positives from CD1-double-negatives in vitro (32). CD1 -3+4+8+ thymocytes are functionally competent and can proliferate in the presence of IL2 (32,33).…”

Section: Discussionmentioning

confidence: 99%

“…CD1 + TCR-CD3+ thymocytes cannot be expanded in vitro, nor can normal peripheral mature CD1 + T cells be detected ex vivo (Table 1; unpublished observations). Interestingly enough, a minor subset (<5%) of CD1-3 + double-positives occurs in vivo We have previously shown that polyclonal activators such as PHA and IL2 stimulate the generation of such CD1-3+ double-positives from CD1-double-negatives in vitro (32). CD1 -3+4+8+ thymocytes are functionally competent and can proliferate in the presence of IL2 (32,33). We therefore conclude that CD1 + and CD1 -, CD4-8-cells can act as precursors for two distinct subsets of doublepositive thymocytes in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…It has been estimated that ~ 95% of thymocytes die mtrathymically, most likely at the inert double-positive thymocyte stage (7,8) It is generally thought that the cells that are eliminated have been tolerized or would never terminally differentiate (7,8). The reason that receptor occupancy leads to clonal deletion in the immature thymocytes, instead of the clonal expansion observed in mature T cells, is unknown, but the occupancy of CD4/CD8 has been implicated in this process (30,34,35) We and others have previously shown that CD1 is covalently associated with CD8 on the surface of double-positive but not mature thymocytes, that functionally competent CD1 + thymomas exist but do not assemble CD1 multimolecular complexes, and that functional CD1 -double-positive thymocytes do exist (13,32,33,36,37). In light of these findings, we shall test the possibility that such CD1 multimolecular complex expression is, perhaps, related to the mechanisms that lead to a selective elimination of immunologically unresponsive cells in the thymus.…”

Section: Discussionmentioning

confidence: 99%

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Delineation of human thymocytes with or without functional potential by CD1-specific antibodies

Hera¹,

Toribio

Martı́nez-A

1989

Int Immunol

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Hematopoletlc precursors lacking T cell antigen receptors (TCR-CD3-) and CD4 and CD8 surface markers (I.e. double-negative thymocytes) give rise to functionally mature T lymphocytes. Yet their major progeny are Immunologlcally unresponsive thymocytes In spite of having acquired TCR -CD3 and CD4 -CD8. Because only mature thymocytes migrate to peripheral lymphold organs and most thymocytes die In situ, the knowledge of the events associated with functional maturation In the double-negative thymocyte progeny Is a fundamental question in T cell development. We reasoned that a clue to trace the fate of early human thymocytes may perhaps come from the study of the developmental acquisition of CD1 antigen, currently used to define better the functionally Inert CD4+8+ (double-positive) stage and absent In mature, medullary thymocytes and peripheral T cells. By using antibodies specific for CD1 (HTA 1/T6) we show here that a large fraction of double-negative thymocytes also express CD1. CD1 +3-, CD1 +3 + , CD1-3+, and CD1-3-subsets all exist. The CD1+3-subset generates CD1+3-4-8+ precursors of CD1 + double-positive cells. A large portion of the CD1 +3+ subset bears TCR75-CD3 complexes. The CD1 -subsets are responsive In assays of function, in which they can be stimulated to use the interleukin 2 pathway of proliferation and to mediate cytotoxiclty. In contrast, all CD1 + thymocytes behave as functionally inert cells. Thus, the CD1 surface marker delineates human thymocyte precursors and their products which lack, or possess, functional potential In vitro, on both a/3 and 76 lineages.

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“…These data underline a critical point in T cell development, namely the growth "signals" involved in the intrathymic differentiation process. In this regard, the expression of receptors for the IL-2 growth molecule in early double-negative thymocytes, shown to contain the precursors of mature T cells (1), has been reported in mouse (47,52) and humans (41), and the potential role of the IL-2 pathway in T cell development has been suggested in both systems (34,(53)(54)(55)(56) .…”

Section: Discussionmentioning

confidence: 99%

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.

Toribio

Hera

Borst

et al. 1988

The Journal of Experimental Medicine

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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.

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Differentiation of human mature thymocytes: Existence of a T3⁺4⁻8⁻ intermediate stage

Cited by 29 publications

References 41 publications

Pathological Findings in Human Autoimmune Lymphoproliferative Syndrome

Pathological Findings in Human Autoimmune Lymphoproliferative Syndrome

Delineation of human thymocytes with or without functional potential by CD1-specific antibodies

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.

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