TCR-independent pathways mediate the effects of antigen dose and altered peptide ligands on Th cell polarization

We examined the role of the peptide/MHC ligand in CD4(+) T cell differentia tion into Th1 or Th2 cells using a TCR alpha beta transgenic mouse specific for hemoglobin (Hb)(64-76)/I-E-k. We identified two altered peptide ligand s of Hb(64-76) that retain strong agonist activity but, at a given dose, in duce cytokine patterns distinct from the Hb(64-76) peptide. The ability of these peptides to produce distinct cytokine patterns at identical doses is not due to an intrinsic qualitative property. Each peptide can induce Th2 c ytokines at low concentrations and Th1 cytokines at high concentrations and has a unique range of concentrations at which these distinct effects occur . The pattern of cytokines produced from limiting dilution of naive T cells demonstrated that the potential to develop an individual Th1 or Th2 cell i s stochastic, independent of Ag dose. We propose that the basis for the obs erved effects on the Th1/Th2 balance shown by the altered peptide ligands a nd the amount of Ag dose involves the modification of soluble factors in bu lk cultures that are the driving force that polarize the population to eith er a Th1 or Th2 phenotype.