Imane Achour

Characterization of the Insulin-Like Growth Factor Axis in the Human Thymus

The components of the insulin‐like growth factor (IGF) axis have been investigated in the normal human thymus. Using ribonuclease protection assays (RPA), IGF‐II transcripts were detected in the normal human thymus. By reverse transcriptase polymerase chain reaction (RT‐PCR) analyses, promoters P3 and P4 were found to be active in the transcription of IGF2 gene within human thymic epithelial cells (TEC). No IGF‐II mRNA could be detected in human lymphoid Jurkat T cells with 30 cycles of RT‐PCR. By Northern blot analyses, IGFBP‐2 to ‐6 (but not IGFBP‐1) were found to be expressed in TEC with a predominance of IGFBP‐4. Interestingly, Jurkat T cells only express IGFBP‐2 but at high levels. The type 1 IGF receptor was detected in Jurkat T cells but not in human TEC. The identification of the components of the IGF axis within separate compartments of the human thymus adds further evidence for a role of this axis in the control of T‐cell development. The precise influence of thymic IGF axis upon T‐cell differentiation and immunological self‐tolerance however needs to be further investigated.

Thymic expression of insulin-related genes in an animal model of autoimmune type 1 diabetes

Insulin and multiple other autoantigens have been implicated in the pathogenesis of autoimmune type 1 diabetes, but the origin of immunological self‐reactivity specifically oriented against insulin‐secreting islet β‐cells remains obscure. The primary objective of the present study was to investigate the hypothesis that a defect in thymic central T‐cell self‐tolerance of the insulin hormone family could contribute to the pathophysiology of type 1 diabetes. This hypothesis was investigated in a classic animal model of type 1 diabetes, the Bio‐Breeding (BB) rat.

Cryptocrine signaling in the thymus network and T cell education to neuroendocrine self-antigens

Both during phylogeny and ontogeny the thymus appears as a nodal point between the two major systems of cell-to-cell signaling, the neuroendocrine and immune systems. This review presents the experimental observations which support a dual role in T cell selection played by the thymic repertoire of neuroendocrine polypeptide precursors. Through the mode of cryptocrine intercellular signaling thymic neuroendocrine-related precursors synthesized in thymic epithelial cells have been shown to influence the early steps in T cell differentiation. In addition, thymic neuroendocrine-related polypeptides are a source of self-antigens which are presented by the major histocompatibility system of the thymic epithelium. Preliminary data also suggest that the intrathymic T cell education to neuroendocrine self-antigens is not strictly superimposible to the antigen presentation by dedicated presenting cells. Insulin-like growth factor-II (IGF-II) was identified as one dominant member of the insulin family expressed by thymic epithelial and nurse cells. The intrathymic presentation of IGF-II or IGF-II derived self-antigens is under current investigation. If further confirmed, the central tolerogenic properties of IGF-II could be considered in the elaboration of a strategy for an efficient and safe prevention of insulin-dependent diabetes.

Cellular and Molecular Aspects of Thymic T-Cell Education in Neuroendocrine Self Principles: Implications for Autoimmunitya

Abstract: Thymic epithelial and nurse cells from different species express a repertoire of neuroendocrine polypeptide precursors. This repertoire exerts a dual role in T‐lymphocyte selection according to their status either as cryptocrine signals or as neuroendocrine self‐antigens of the peptide sequences that are processed from those precursors then presented to pre‐T cells. Thymic neuroendocrine self‐antigens correspond to peptide sequences highly conserved throughout evolution of their family. Though thymic MHC class I molecules are involved in the processing of thymic neuroendocrine self‐antigens, preliminary data show that their presentation to pre‐T cells is not allelically restricted. Thymic T‐cell education in neuroendocrine families also implies that the structure of a given family may be presented to pre‐T cells. Our studies have evidenced the homology between thymic neuroendocrine‐related self‐antigens and dominant T‐cell epitopes of peripheral neuroendocrine signals (neuroendocrine autoantigens). The biochemical difference between neuroendocrine autoantigens and homologous thymic self‐antigens might explain the opposite immune responses evoked by those two types of antigens (activation and memory induction vs. tolerogenic effect). Altogether, these studies support the therapeutic use of thymic neuroendocrine self‐antigens in reprogramming the immunological self‐tolerance that is broken in autoimmune endocrine diseases like insulin‐dependent diabetes type I. As recently stated by P. M. Allen in an important review, the fate of developing T lymphocytes in the thymus is influenced by the numerous types of peptidic interactions within the thymic cellular environment. 1 To define the precise nature of thymic cells and naturally occurring biochemical peptide signals involved in positive and negative selection of immature T cells has become a prominent objective for the future research efforts in thymic physiology. This paper will try to show how thymic neuroendocrine‐related peptides synthesized and processed within the thymic microenvironment indeed can play a role both in the development of the peripheral T‐cell repertoire and in the death of randomly rearranged, self‐reactive T cells.

Developmental and evolutionary aspects of thymic T-cell education to neuroendocrine self

Thymic epithelial cells, including nurse cells (TECs/TNCs), from various species synthesize neuroendocrine-related precursors belonging to neurohypophysial, tachykinin and insulin hormone families. The thymic repertoire of neuroendocrine-related polypeptides illustrates at the molecular level the paradoxical role of the thymus in both T cell positive and negative selection. On the one hand, these precursors are a source of signals which interact with neuroendocrine-type receptors expressed by target pre-T cells according to the cryptocrine type of cell-to-cell signaling. On the other hand, the same precursors constitute a source of self-antigens which are presented to pre-T cells by the thymic major histocompatibility complex system. Basically, the model of thymic T cell education to neuroendocrine self was established by the identification in TECs/TNCs of immunoreactive (ir) oxytocin as the self-antigen of the neurohypophysial family. Nevertheless, through the expression in TECs/TNCs of ir-neurokinin A and ir-insulin-like growth factor-II, the model also applies to the tachykinin and insulin hormone families.