CD4 T cells activated in vivo in response to human collagen type IV (hCol IV) resemble either T helper type 1 (Th1) or Th2 cells depending on the major histocompatibility complex (MHC) class II genotype of the responding mice. H-2s mice were shown to selectively activate Th1-like cells, releasing interleukin (IL 2 and interferon-gamma in response to hCol IV, whereas H-2b.d mice were shown to selectively activate Th2-like cells, releasing IL 4 and IL 5 in response to hCol IV. These results suggested that MHC class II regulated the type of effector function observed during an immune response. It was of interest to determine if the functional difference observed between the CD4 T cells of the two strains was due to the presentation of different peptides of the hCol IV molecule by the two MHC class II molecules. The present results demonstrate that a single peptide of the collagen IV molecule will elicit a Th1-like response in H-2s strains and Th2-like responses in H-2b.d strains, as was observed when using the intact hCol IV molecule. Furthermore, the failure to generate Th1-like responses in H-2b.d could be overcome by increasing the dose of this peptide in vitro. Compared to H-2s, the Th1-like response in H-2b required 100 times the amount of peptide to reelicit an equivalent response. These data suggest that a single peptide of hCol IV can control the type of effector response observed.