A Unique Thymic Fibroblast Population Revealed by the Monoclonal Antibody MTS-15

Abstract

T cell differentiation in the thymus is dependent upon signals from thymic stromal cells. Most studies into the nature of these signals have focused only on the support provided by the thymic epithelium, but there is an emerging view that other stromal cells such as mesenchymal fibroblasts may also be involved. Study of the latter has been hindered by a lack of appropriate markers, particularly those allowing their isolation. In this study, we describe a new surface marker of thymic stroma, MTS-15, and demonstrate its specificity for fibroblasts and a subset of endothelial cells. Coculture experiments showed that the determinant could be transferred between cells. Extensive biochemical analysis demonstrated that the Ag bound by MTS-15 was the glycosphingolipid Forssman determinant, consistent with the distribution observed. Transcriptional analysis of purified MTS-15+ thymic fibroblasts revealed a unique expression profile for a number of chemokines and growth factors important to thymocyte and epithelial cell development. In a model of cyclophosphamide-induced thymic involution and regeneration, fibroblasts were found to expand extensively and express growth factors important to epithelial proliferation and increased T cell production just before thymic regeneration. Overall, this study identifies a useful marker of thymic fibroblasts and highlights this subpopulation as a key player in thymic function by virtue of their support of both thymocytes and epithelial cells.

Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity

“…It is well reported that fibroblasts play an important role in TEC development (31,32). Consistent with an overall reduction in CD45 Ϫ stromal cells, we found a 2-fold reduction in the number of fibroblasts stained by the Ab MTS15 in 3-to 6-wk-old NZB mice (Fig.…”

“…The lack of medullary expansion is commensurate with a lack of relevant mesenchymal growth factors due to reduced numbers of the relevant mesenchymal fibroblast subset (MTS15 ϩ ) (31). Alternatively, fibroblast number may be reduced secondary to, or even because of, an independent reduction in TEC, although the presence and expansion of fibroblasts in TECdeficient, castrated rag Ϫ/Ϫ mice (26) would seem to preclude this.…”

FGFR2IIIb signaling regulates thymic epithelial differentiation

“…Persistence of the FGFR2IIIb, FGF7, and FGF10 in the postnatal thymus (Erickson et al, 2002;Gray et al, 2007;Rossi et al, 2007b) provides circumstantial evidence that this signaling pathway continues to play a role in the maintenance of the adult thymic environment. Exogenous FGF7 can ameliorate the deleterious effects of pretransplantation conditioning regimens on thymic function, increasing thymic cellularity and restoration of the peripheral T-cell pool (Panoskaltsis-Mortari et al, 1998;Min et al, 2002;Alpdogan et al, 2006) and can also partially reverse the agerelated declines of thymic cellularity and function in aged mice (Alpdogan et al, 2006;Min et al, 2007).…”

Short-term inhibition of p53 combined with keratinocyte growth factor improves thymic epithelial cell recovery and enhances T-cell reconstitution after murine bone marrow transplantation

“…11 Conditioning depletes TECs, impairing T-cell production for prolonged periods of time after BMT. [14][15][16][17] Restoring thymic function would speed peripheral T-cell recovery after BMT.Developing thymocytes can be distinguished by their CD4 and CD8 cell surface expression. CD4 Ϫ CD8 Ϫ (double-negative, DN) thymocytes mature to become CD4 ϩ CD8 ϩ (double-positive, DP) thymocytes and undergo positive selection on cortical TECs (cTECs).…”