A defining juncture in the life of a T cell is its encounter with its cognate Ag, resulting finally in effector and/or memory T cells known to express, among other characteristics, increased surface levels of CD44. The requirements for the "activation" of CD44 to bind its major ligand, hyaluronan (HA), and the in vivo role of this interaction remain unresolved. We have recently proposed that the CD44/HA interaction is involved in primary lymphocyte adhesion, leading to extravasation at inflammatory sites. We show here that activation of CD44 and ability to engage in rolling occurs directly through polyclonal as well as Ag-specific TCR-initiated signaling. Using a superantigen, it is primarily the Ag-specific activated Vbeta-bearing cells that are induced to bind HA. In addition, this CD44 activation does not appear to be the result of overt changes in glycosylation. These results connect activation of CD44 on T cells with the initiation of immune responses and suggest potential roles for the CD44/HA interaction.