Interaction of merosin (laminin 2) with very late activation antigen‐6 is necessary for the survival of CD4⁺ CD8⁺ immature thymocytes

Abstract

SUMMARYThe laminin a2-chain is a component of merosin, a member of the laminin family molecules, which is mainly expressed in the basement membranes of striated muscle. It is known that laminin a2 gene (lama2) null mutant mice (dy 3k /dy 3k ) exhibit congenital muscular dystrophy (CMD). Because the laminin a2-chain is also expressed in the thymus, the role of merosin in the thymus was examined. In association with the onset of muscular dystrophy, CD4+ CD8 + double-positive (DP) thymocytes disappear by apoptotic cell death, while CD4 + CD8 ± or CD4 ± CD8 + thymocytes remain. In order to study the mechanisms leading to the selective death of DP cells in the absence of merosin, the role of the interaction between very late activation antigen-6 (VLA-6), a candidate merosin ligand in the thymus, and merosin was examined. The in vitro survival of thymocytes from normal mice was maintained by the addition of either anti-VLA-6 monoclonal antibodies (mAbs) or merosin. Furthermore, when the normal thymocytes were cultured on thymic epithelial cell lines, viable DP cell recoveries on wild-type epithelial cells were better than on cells from null mutant mice. The results suggest that DP cells are more sensitive to an uncharacterized apoptotic death signal, and that survival is supported by the interaction between VLA-6 and merosin.

Functional Diversity of Laminins

“…Lack of α2 laminin impairs thymus development by reducing the amount of T cell progenitors, especially DP cells (Iwao et al 2000, Magner et al 2000. In vitro, LM-211 supports the survival of thymocytes (Iwao et al 2000). Laminins appear to have significant roles in the migration and inflammation of immune cells.…”

“…In vitro, DN cells adhere strongly to α5 laminins, unlike DP cells, which reside within the cortex (Kutlesa et al 2002). Lack of α2 laminin impairs thymus development by reducing the amount of T cell progenitors, especially DP cells (Iwao et al 2000, Magner et al 2000. In vitro, LM-211 supports the survival of thymocytes (Iwao et al 2000).…”

Regulation of the Immune System by Laminins

“…In vitro , laminin 211 isolated from placenta favors the proliferation of anti-CD3-activated thymocytes via the integrins α3β1 and α6β1 [58]. This laminin isoform seems to regulate apoptosis as an increased number of apoptotic thymocytes has been observed in the thymic capsular and subcapsular regions in dy/dy mice [57] and increased apopototic cell death of the double-positive thymocytes in laminin α2-chain null mutant mice dy3k/dy3k [59]. The absence of laminin 211 has no effect on the apoptosis of mature single-positive thymocytes.…”

Laminin isoforms of lymph nodes and predominant role of α5-laminin(s) in adhesion and migration of blood lymphocytes

“…Studies with these tools have demonstrated a characteristic distribution of laminin isoforms in thymus and participation of ␣2-, ␣3-, and ␣5-laminins in adhesion, migration, proliferation, survival, and/or development of thymocytes and T cell malignancies [20,[25][26][27][28][29][30][31]. Moreover, adhesion and migration of neoplastic lymphocytes have been found to be promoted by ␣4-and ␣5-laminins [32,33].…”