Provided are HLA pan DR-binding peptides and methods of using such peptides to modulate, block, or inhibit immune responses to effect treatment of immune-mediated diseases and conditions, such as inflammatory and autoimmune diseases, cancer, and microbial infections. These peptides and methods are also useful diagnostically to screen peptide or peptide analogs that can inhibit the pathogenic immune response or up-regulate an immune response against aberrant or invading cells, to monitor efficacy for therapeutic treatments, and to identify other agents that may be effective to inhibit or otherwise modulate an immune response such as by altering T cell functional phenotype, and even more particularly by modulating the regulatory phenotype of regulatory T cells and/or inducing emergence of T cells with a different functional phenotype.