Thymic microenvironments, 3-D versus 2-D?

In the present work, we have demonstrated in vivo an altered maturation of the thymic epithelium that results in defective T cell development which increases with age, in the thymus of Eph A4-deficient mice. The deficient thymi are hypocellular and show decreased proportions of double-positive (CD4+CD8+) cells which reach minimal numbers in 4-wk-old thymi. The EphA4 −/− phenotype correlates with an early block of T cell precursor differentiation that results in accumulation of CD44−CD25+ triple-negative cells and, sometimes, of CD44+CD25− triple-negative thymocytes as well as with increased numbers of apoptotic cells and an important reduction in the numbers of cycling thymocytes. Various approaches support a key role of the thymic epithelial cells in the observed phenotype. Thymic cytoarchitecture undergoes profound changes earlier than those found in the thymocyte maturation. Thymic cortex is extremely reduced and consists of densely packed thymic epithelial cells. Presumably the lack of forward Eph A4 signaling in the Eph A4 −/− epithelial cells affects their development and finally results in altered T cell development.

Section: Cd25mentioning

confidence: 98%

Thymic Alterations in EphA4-Deficient Mice

Múñoz

Alfaro

García‐Ceca

et al. 2006

“…Organization and differentiation of thymic stromal cells into distinct microenvironments with a typical cellular architecture are subject to inductive signals provided by thymocytes (6,11,46). In particular, the comparison of two mouse strains, Tg⑀26 and RAG null mice, has been most informative in revealing the identity of the thymocyte subpopulation critical for the formation of a normal thymic microenvironment: TN II and/or TN III thymocytes provide signals that induce the three-dimensional organization of TEC (11).…”

Section: Induction Of a Prototypical Thymic Microenvironment Is A Prementioning

confidence: 99%

“…Notably, the organization of the thymic epithelium differs from most other epithelial organs in the body: rather than forming a sheet of cells positioned on a basement membrane, thymic epithelial cells (TEC) form a three-dimensional meshwork (6).…”

mentioning

confidence: 99%

Normal Thymic Architecture and Negative Selection Are Associated with Aire Expression, the Gene Defective in the Autoimmune-Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED)

Žuklys

Balc̆iūnaite

Agarwal

et al. 2000

234

159

T cell development is tightly controlled by thymic stromal cells. Alterations in stromal architecture affect T cell maturation and the development of self-tolerance. The monogenic autoimmune syndrome APECED (autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy) is characterized by the loss of self-tolerance to multiple organs. Although mutations in the autoimmune regulator (AIRE) gene are responsible for this disease, the function of AIRE is not known. Here we report on the spatial and temporal pattern of murine Aire expression during thymic ontogeny and T cell selection. Early during development, thymic Aire transcription is critically dependent on RelB and occurs in epithelial cells in response to lymphocyte-mediated signals. In adult tissue, Aire expression is confined to the medulla and the corticomedullary junction, where it is modulated by thymocytes undergoing negative selection. Aire may determine thymic stromal organization and with it the induction of self-tolerance.

“…However, the in vitro culture system of FTOC did not allow us to examine whether the newly generated CD4 ϩ CD8 Ϫ thymocytes could emigrate the thymus to supply CD4 T cells in the periphery. It was also unclear whether the formation of the medullary region might be affected upon the Ab treatment that restores the generation of CD4 ϩ CD8 Ϫ thymocytes, because the architecture of the thymus in the FTOC condition is severely damaged and devoid of clear cortex-medulla structure (17). have shown that the in vivo treatment with a hybrid Ab consisting of anti-V␤8 Ab and anticortical epithelial cell Ab rescues the generation of V␤8 ϩ CD4 ϩ CD8 Ϫ thymocytes in class II MHC-deficient mice.…”

Section: Ifferentiation Of Immature Cd4mentioning

confidence: 99%

In Vivo Treatment of Class II MHC-Deficient Mice with Anti-TCR Antibody Restores the Generation of Circulating CD4 T Cells and Optimal Architecture of Thymic Medulla

Nasreen

Ueno

Saito

et al. 2003

TCR ligation by the self-peptide-associated MHC molecules is essential for T cell development in the thymus, so that class II MHC-deficient mice do not generate CD4+CD8− T cells. The present results show that the administration of anti-TCR mAb into class II MHC-deficient mice restores the generation of CD4+CD8− T cells in vivo. The CD4 T cells were recovered in the thymus, peripheral blood, and the spleen, indicating that the anti-TCR treatment is sufficient for peripheral supply of newly generated CD4 T cells. Unlike peripheral CD4 T cells that disappeared within 5 wk after the treatment, CD4+CD8− thymocytes remained undiminished even after 5 wk, suggesting that CD4 T cells in the thymus are maintained separately from circulating CD4 T cells and even without class II MHC molecules. It was also found that the mass of medullary region in the thymus, which was reduced in class II MHC-deficient mice, was restored by the anti-TCR administration, suggesting that the medulla for CD4+CD8− thymocytes is formed independently of the medulla for CD4−CD8+ thymocytes. These results indicate that in vivo anti-TCR treatment in class II MHC-deficient mice restores the generation of circulating CD4 T cells and optimal formation of the medulla in the thymus, suggesting that anti-TCR Ab may be useful for clinical treatment of class II MHC deficiencies.