Peptide-based instruction of suppressor commitment in naïve T cells and dynamics of immunosuppression in vivo

Recent years have witnessed the revival of suppressor T cells that control immunity by interfering with the generation of effector T-cell function in vivo. The discovery that CD4 T cells with the CD25 surface marker were enriched in suppressor activity enabled further phenotypic and functional analysis of the so-called natural suppressor cells. In vitro characterization showed that these cells were anergic, i.e. did not respond to antigenic stimulation with proliferation and, instead they suppressed other cells through direct cell contact resulting in inhibition of interleukin-2 gene transcription. We have analysed the generation and function of suppressor T cells in T-cell receptor (TCR) transgenic mice. The results showed that such cells can be generated intrathymically when agonist TCR ligands are expressed on thymic epithelial cells. Thus generated cells constitute a lineage of cells committed to suppression only with the ability to survive for prolonged periods of time in the absence of the inducing ligand. Because of appropriate homing receptors such cells can accumulate and proliferate in antigen draining lymphnodes after antigenic stimulation and suppress proliferation and cytokine secretion of CD4 and CD8 T cells as well as CD8 T-cell-mediated cytotoxicity. We also attempted to generate such cells from naïve T cells in secondary lymphoid tissue under conditions where expansion of already preformed suppressor T cells could be excluded. The results showed that subimmunogenic peptide delivery by osmotic minipumps or by peptide containing DEC 205 antibodies yielded CD25+ suppressor cells that were phenotypically and functionally indistinguishable from intrathymically generated suppressor cells. The experiments with DEC205 antibodies revealed (i) dose-dependent proliferation of naïve T cells and (ii) conversion into suppressor T cells of only those T cells that underwent a limited number of cell divisions. These results are compatible with other studies that were, however, less rigorous in excluding expansion of existing cells as opposed to de novo generation of suppressor cells from naïve T cells. The fact that natural suppressor cells have an essential role in preventing autoimmunity and that they can be specifically induced by TCR agonist ligands opens new perspectives in preventing autoimmunity, transplant rejection and allergy.