Normal T Cell Development in the Absence of Thymic Insulin Expression

Abstract

Ectopic expression of insulin in thymus has been suggested to be involved in tolerance induction against pancreatic beta cells and in type 1 diabetes (T1D) pathogenesis. However, it is not known whether thymic insulin expression would also influence thymocyte maturation and differentiation. To address these questions, we have used mice that are insulin deficient. Early fetal thymi were cultured in fetal thymic organ cultures (FTOCs) and the development of thymocytes was studied by flow cytometry. The results revealed no significant difference in thymocyte maturation in the absence of thymic insulin. Taken together, these data do not support a role for thymic insulin in thymocyte differentiation and growth.

Ultrastructure of the thymus in diabetes mellitus and starvation

“…[2][3][4][5][6] Hypotheses for the cause of the immune dysfunction underlying type 1 diabetes include self-reactive T-cell clones that either escape deletion in the thymus, escape from peripheral tolerance, or escape from homeostatic control -all are scenarios that can create an alteration in the immune balance and consequently lead to autoimmunity. 7,8 The T lymphocytes that fulfil thymus education requirements in the thymus, i.e. T lymphocytes that are able to appropriately attack a 'foreign' antigen, are important in the body's defence against viral and fungal infections.…”

Evidence for De Novo Expression of Thymic Insulin by Peripheral Bone Marrow‐derived Cells

“…The two mouse strains deficient in Ins1 and Ins2 were kindly provided by Dr J. Jamie (Institute Cochin, Paris, France) and kept under standard conditions at Malmö University Hospital animal facility. Mice were crossed and genotyped as described before [25]. Briefly, the mice were first intercrossed to generate Ins1 ) ⁄ + Ins2 + ⁄ ) and Ins1 ) ⁄ ) Ins2 + ⁄ ) , which were further intercrossed in order to generate double knockout embryos.…”

“…However, since insulin deficient mice die during the first 48 h after birth, we have focused on fetal thymi to study T-cell development and selection in an environment without insulin. We have previously shown that lack of insulin doesn't affect thymocytes development and differentiation based on thymocyte subsets frequency and distribution [25]. Here we expanded our study and investigated the mechanisms contributing to thymic insulin expression.…”

“…Therefore we have used fetal thymi to study thymocyte development and selection. We have previously shown that the lack of thymic insulin does not affect thymocyte development per se suggesting that thymic insulin expression is dispensable for thymocytes differentiation allowing an unbiased analysis when comparing the results with wt mice [25]. Here we show that transplantation of Ins1 ) ⁄ ) Ins2 ) ⁄ ) thymi under the kidney capsule of insulin-expressing mice results in thymic insulin re-expression implicating that peripheral bone marrow-derived cells capable of transcribing insulin are migrating from the periphery and could contribute to thymocyte selection.…”

Abnormal T-Cell Development in the Thymus of Non-obese Diabetic Mice: Possible Relationship With the Pathogenesis of Type 1 Autoimmune Diabetes

“…Despite that, proinsulin gene is naturally expressed at low levels in fetal and postnatal thymi in humans, rats and mice ( 22 ). Although the expression of proinsulin in the thymus is not necessary for T cell differentiation and growth ( 23 , 24 ), variations in the expression of the insulin gene in the thymus, but not in the pancreas, in both humans and mice, can modulate self-tolerance to insulin, with the expression levels being inversely correlated with T1D susceptibility ( 21 , 25 ).…”