Regulatory T cells in the establishment and maintenance of self-tolerance: role of the thymic epithelium

Abstract

The thymus constitutes the microenvironment for T lymphocyte differentiation and acquisition of self-tolerance. Aiming to specify the contributions of the two essential parts of the thymus, namely hemopoietic and epithelial, we have devised experimental models in birds and mice. Chimeric thymuses, xenogeneic in birds and allogeneic in mice, were constructed early in development. In both models we could demonstrate a critical role of the epithelial component of the thymic stroma in induction and maintenance of self-tolerance. These experiments showed that suppression mechanisms are also implicated in these events, strongly suggesting the existence of regulatory T cells in both models. Before these experiments the control of selftolerance was usually attributed to suppressive cells. However, as the cell phenotypes were not identified, the role of these cells was disregarded. Numerous studies since our investigations argue in favour of regulatory mechanisms. The work we initiated several years ago represents a contribution to our understanding of the two linked and opposite aspects of immune-responded control, namely self-tolerance and autoimmunity.

FOXN1 recombinant protein enhances T‐cell regeneration after hematopoietic stem cell transplantation in mice

“…We have also shown that the number of Treg cells and iNKT cells was increased in rFOXN1-treated HSCT recipients. Our results are consistent with reports that TECs support the development of natural Treg cells [47,48] and that iNKT cell development requires interactions with TECs [49].…”

“…We have also shown that the number of Treg cells and iNKT cells was increased in rFOXN1-treated HSCT recipients. Our results are consistent with reports that TECs support the development of natural Treg cells [47,48] and that iNKT cell development requires interactions with TECs [49].Our results that GVHD was not observed in rFOXN1-treated allogeneic HSCT recipients suggest that the precursors of these newly formed T cells had undergone normal negative selection in the thymus of the allogeneic HSCT recipients, leading to immune tolerance to the donor and host antigens. However, although GVHD did not occur in our current T-cell-depleted HSCT model, it will be important to determine whether rFOXN1 affects the development of GVHD in a T-cell replete allogeneic setting, which is underway in our laboratory.…”

“…The FOXN1-TAT gene was amplified using the sense primer above and antisense primer 5 -CTCGAGTCAGCGGCGGCGCT GGCGGCGTTTCTTGCGGCCATAAGCCAGAGCCAATGGCTTTG-3 encoding YGRKKRRQRRR from the HIV TAT [47][48][49][50][51][52][53][54][55][56][57] . The entire DNA fragment for FOXN1-TAT was cloned into the expression vector pET-45b(+) (Novagen, Gibbstown, NJ, USA) using the In-Fusion Advantage PCR Cloning Kit (Clontech, Mountain View, CA, USA) with two primers (5 -CCATCACGTGGGTACCGTGTCGC TACTCCC-3 and 5 -CTTTACCAGACTCGAGTCAGCGGCGGCGCT-3 ) according to the manufacturer's instructions.…”

“…The use of rFOXN1 protein may overcome these adversities. Because the cell-penetrating peptides or protein transduction domain (PTD) embedded in the HIV transactivator of transcription (TAT) protein (amino acids [47][48][49][50][51][52][53][54][55][56][57] has been shown to successfully mediate the induction of protein into mammalian cells in vitro and in vivo [28,29], we cloned and expressed rFOXN1 protein fused with TAT PTD. We demonstrate here that the rFOXN1 can enter the cytoplasm and nucleus.…”

The Nogent Institute - 50 Years of Embryology

“…Tolerance mediated by these cells is «active», differently from the widely accepted dogma of the default mechanism, i.e., autoreactive cell elimination in the thymus. This work was recorded in a series of papers (see for review Le Salaün et al, 2005 …”