T‐Cell Lineages, Repertoire Selection and Tolerance Induction

MacDonald, H. Robson; Howe, Rawleigh; Pedrazzini, Thierry; Lees, Rosemary K.; Budd, Ralph C.; Schneider, R; Liao, Nan‐Shih; Zinkernagel, Rolf M.; Louis, Jacques; Raulet, David H.; Hengartner, Hans; Miescher, G

doi:10.1111/j.1600-065x.1988.tb00762.x

Cited by 64 publications

(49 citation statements)

References 84 publications

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“…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%

“…In our previous studies we removed the CD1 + population from isolated CD4-8-thymocytes prior to culture and hence did not find CD1 +4+8+ thymocytes (3). Similarly, in the mouse it was shown that only the IL2-R-, Thy-I 1 * subset of CD4-8-thymocytes generates immature CD4+8+ cells in vitro (30,31). 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.…”

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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Hera¹,

Toribio

Martı́nez-A

1989

Int Immunol

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“…Since both T cell precursors and thymic stroma express CD44, we could not delineate the mechanisms underlying the effect of the anti-CD44 mAbs. The mechanism by which accessory cells participate in the CD44 co-mitogenic effects on T cells needs to be studied, especially as thymic stroma is normally required for T cell differentiation (1)(2)(3)35). CD7 + , CD1 -2-3-4-8-14-16-20-early thymocytes can be expanded using polyclonal activators in the absence of thymic stroma without differentiation.…”

Section: Discussionmentioning

confidence: 99%

Function of CD44(Pgp-1) homing receptor in human T cell precursors

Hera¹,

Acevedo²,

Marston³

et al. 1989

Int Immunol

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T cell precursors migrate from extrathymlc hematopoietic tissues and differentiate after encountering the thymic mlcroenvlronment. We asked whether human T cell precursors express the CD44(Pgp-1/gp90HR) class of homing receptors that have been implicated in the traffic of hematopoietic cells, such as lymphocyte entry to peripheral lymphoid organs. Flow cytometry and immunopreclpltatlon studies demonstrate that CD7+34+, CD1 -2-3-4-8-14-16-20-cells In bone marrow and thymus, which have been shown to exhibit features of T cell precursors, bear CD44. Immunohlstologlcal studies show that clusters of thymocytes in the subcapsular and the Inner cortex and most medullary thymocytes are clearly CD44 + , whereas the expression of CD44 is selectively downregulated in CD3-and CD3 low functionally Incompetent cortical thymocytes. The expression of CD44 Is not restricted to T cell precursors but also occurs In thymic stroma, which bear a different molecular species of CD44. CD44-specific antibodies exert stimulatory effects on T cell precursors, a process that is dependent on stromal cells. We postulate that CD44 might be an adhesion molecule for precursor homing to thymus and that it participates In cell-to-cell interactions within the thymic environment.

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“…Medulla proteins of the major histocompatibility complex (MHC), or the cluster differentiation (CD) markers CD4 and CD8, which are co-receptors of TCR [32]. Other markers such as CD25, CD3 and CD44 are very useful to define stages of intrathymic T-cell differentiation.…”

Section: Cortexmentioning

confidence: 99%

Impact of the Somatotrope Growth Hormone (GH)/Insulin-Like Growth Factor 1 (IGF-1) Axis Upon Thymus Function: Pharmacological Implications in Regeneration of Immune Functions

Goffinet¹,

Mottet²,

Kermani³

et al. 2011

IEMAMC

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Abstract:The thymus is the central lymphoid structure where T-cell differentiation takes place, and a crucial organ for the maintenance of homeostasis in the immune system. Thymopoiesis includes intrathymic proliferation of T-cell precursors, selection and output of both self-tolerant and competent effector T cells, as well as of natural regulatory T cells (nTreg). In the crosstalk between the neuroendocrine and immune systems, peptide hormones have been more and more implicated in immunomodulation for the last thirty years. The somatotrope growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in particular has been repeatedly shown to play a major regulatory role upon thymus function and T-cell development. This review will focus on the important thymotropic properties of the somatotrope GH/IGF-1 axis, and will try to discriminate these properties in function of the endocrine or paracrine/autocrine pathways involved in their mediation. Most importantly, in light of an increasing number of recent studies, GH and IGF-1 now appear as novel therapeutic agents that could be used for enhancing thymopoiesis in different cases of immune deficiencies, including aging-related immune dysfunction.Keywords: Thymus, growth hormone (GH), insulin-like growth factors (IGFs), HIV, growth hormone deficiency (GHD), Chagas disease. GENERAL INTRODUCTIONThe thymus is now considered as a crucial organ for maintenance of immune system homeostasis and the central lymphoid organ where occurs the generation of self-tolerant and competent naive T cells, as well as self-antigen specific natural Treg cells [1,2]. However, for a long time, the thymus has been regarded as an endocrine gland. In addition, the thymus now appears as a privileged site where the endocrine and immune systems intimately interact.A permanent crosstalk exists between the neuroendocrine and immune systems [3][4][5][6]. In addition to the strong modulation of immunity by glucocorticoids and sexual steroids, other hormones have been more and more involved in immunomodulation. Indeed, the somatotrope GH/IGF-1 axis, as well as prolactin and thyroid hormones [7], were shown to play an important regulatory role in T-cell development [8][9][10].GH is mainly synthesised in the anterior pituitary gland but can also be produced by immune cells [11,12]. GH has several biological actions in the immune system including regulation of thymopoiesis and T-cell development [13]. Nevertheless, it is uneasy to distinguish whether the thymotropic effects of GH are direct or mediated by IGF-1, as most *Address correspondence to this author at the University of Liege Center of Immunoendocrinology (CIL), Institute of Pathology CHU-B23, B-4000 Liege-Sart Tilman, Belgium; Tel: +32 43 66 25 50; Fax: +32 43 66 98 59; E-mail: vgeenen@ulg.ac.be of GH effects are driven by induction of IGF-1 and as IGF-1 has also been described as an endogenous factor in the thymic microenvironment [12]. The evolution of the research field has brought new insights that justify an overview update as some ancie...

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T‐Cell Lineages, Repertoire Selection and Tolerance Induction

Cited by 64 publications

References 84 publications

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

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

Function of CD44(Pgp-1) homing receptor in human T cell precursors

Impact of the Somatotrope Growth Hormone (GH)/Insulin-Like Growth Factor 1 (IGF-1) Axis Upon Thymus Function: Pharmacological Implications in Regeneration of Immune Functions

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