Novel mechanisms of glucocorticoids in the treatment of multiple sclerosis

wildtype peptide SIINFEKL or its altered peptide ligand variants (APLs) exhibiting decreased affinities (SIINFEKL N SIYNFEKL N SIIQFEKL N SIIVFEKL). As read out, we assessed TF-mediated changes of the proliferative T cell response as well as T effector functions. Using the setup described above we could demonstrate that the extent of TFmediated suppression of T cell proliferation correlated with the affinity of the stimulatory antigen, i.e. TF exerted strong suppressive effects upon high-affinity TCR stimulation but only modest suppressive effects upon low-affinity TCR stimulation. Importantly, under these conditions, the proliferative response to different antigen affinities per se in the absence of TFwas comparable.Moreover, TF-mediated suppressionwas more pronounced employing higher antigen concentrations. Our results provide for the first time experimental evidence of affinity-dependent effects of a drug employed for control of T cell mediated autoimmunity. Hence,we propose that TF is not a global immune suppressor but rather acts as a selective immune-modulator, which preferentially interferes with the expansion of high affinity T cell clones while in parallel permitting low-affinity-triggered T cell responses. This is the first description of a novel sophisticated mechanism of selective immunemodulation depending on the quality of T cell activation.