The extracellular domain of CD4 regulates the initiation of T cell activation

To assess the respective contribution of the extracellular and intracellula r domains of CD4 in regulating early T cell activation events, we have used a CD4-independent murine T cell clone transfected with human CD4. Stimulat ion of CD4 positive clones could only be observed if CD4 molecules associat ed to lck were co-aggregated with the TCR complex, confirming that the simu ltaneous interaction of MI-IC class II molecules with the CD4/lck complex a nd the TCR is required to initiate T cell activation. To assess the involve ment of the extracellular portion of CD4 in this process, we transfected a chimeric molecule (EGFRCD4) consisting of the extracellular portion of the epidermal growth factor receptor (EGFR), and of the transmembrane and cytop lasmic domains of human CD4. Although this chimeric molecule associates wit h lck, transfected clones were induced to proliferate by mAb specific for T CR in the absence of co-aggregation. A new regulatory role for the extracel lular domain of CD4 which is independent of its interaction with MHC class II molecules is thus revealed in these experiments. Taken together, our res ults demonstrate that, in a CD4-independent cell line, two domains of CD4 r egulate early T cell activation events: (1) its association with lck and (2 ) its extracellular domain, independently of its interaction with MHC class II molecules. (C) 2000 Published by Elsevier Science Ltd.