CONSTITUTIVE ACTIVATION OF INTEGRIN ALPHA-4-BETA-1 DEFINES A UNIQUE STAGE OF HUMAN THYMOCYTE DEVELOPMENT

Our understanding of thymocyte development and of the positive and neg ative 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 contr ol the homing and population of the thymus by T cell precursors and th e subsequent migration of developing thymocytes through the thymic arc hitecture. As the integrins represent a candidate group of cell surfac e receptors that may regulate thymocyte development, we have analyzed the expression and function of alpha 4 beta 1 and alpha 5 beta 1 on hu man thymocytes. A major portion of double positive (CD4(+)CD8(+)) huma n thymocytes express alpha 4 beta 1 in a constitutively active form an d adhere to fibronectin and vascular cell adhesion molecule 1. alpha 4 beta 1 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 an d low levels of CD3 and CD69. In contrast, nonadherent cells possess t he phenotype of thymocytes after positive selection, expressing interm ediate levels of CD4 and/or CD8 and high levels of CD3 and CD69. The a dherent population fails to respond to activation with anti-CDS and fi bronectin, whereas nonadherents exhibit an alpha 5 beta 1-dependent pr oliferation. Differential regulation of alpha 4 beta 1 and alpha 5 bet a 1 receptors may provide a mechanism controlling cellular traffic, di fferentiation, and positive selection of thymocytes.