Constitutive activation of integrin α4β1 defines a unique stage of human thymocyte development

Abstract

Our understanding of thymocyte development and of the positive and negative selection events involved in shaping the repertoire of mature T lymphocytes has been greatly facilitated by the use of transgenic and gene knockout animals. Much less is known about the factors that control the homing and population of the thymus by T cell precursors and the subsequent migration of developing thymocytes through the thymic architecture. As the integrins represent a candidate group of cell surface receptors that may regulate thymocyte development, we have analyzed the expression and function of α4β1 and α5β1 on human thymocytes. A major portion of double positive (CD4+CD8+) human thymocytes express α4β1 in a constitutively active form and adhere to fibronectin and vascular cell adhesion molecule 1. α4β1 expression is similar on adherent and nonadherent populations, thus, activity reflects the receptor state and not simple expression. The adherent cells are immature, expressing high levels of CD4/CD8 and low levels of CD3 and CD69. In contrast, nonadherent cells possess the phenotype of thymocytes after positive selection, expressing intermediate levels of CD4 and/or CD8 and high levels of CD3 and CD69. The adherent population fails to respond to activation with anti-CD3 and fibronectin, whereas nonadherents exhibit an α5β1-dependent proliferation. Differential regulation of α4β1 and α5β1 receptors may provide a mechanism controlling cellular traffic, differentiation, and positive selection of thymocytes.