Abstract
Thymus-derived CD4(+)CD25(+) regulatory T cells suppress autoreactive CD4(+) and CD8(+) T cells and thereby protect from autoimmunity. In animal models, adoptive transfer of CD4(+)CD25(+) regulatory T cells has been shown to prevent and even cure autoimmune diseases as well as pathogenic alloresponses after solid organ and stem-cell transplantations. We recently described methods for the ...
Abstract
Thymus-derived CD4(+)CD25(+) regulatory T cells suppress autoreactive CD4(+) and CD8(+) T cells and thereby protect from autoimmunity. In animal models, adoptive transfer of CD4(+)CD25(+) regulatory T cells has been shown to prevent and even cure autoimmune diseases as well as pathogenic alloresponses after solid organ and stem-cell transplantations. We recently described methods for the efficient in vitro expansion of human regulatory T cells for clinical applications. We now demonstrate that only CCR7- and L-selectin (CD62L)-coexpressing cells within expanded CD4(+)CD25(high) T cells maintain phenotypic and functional characteristics of regulatory T cells. Further analysis revealed that these cells originate from D45RA(+) naive cells within the CD4(+)CD25(high) T-cell compartment, as only this subpopulation homogeneously expressed CD62L, CCR7, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), and forkhead box P3 (FOXP3), produced no inflammatory cytokines; and maintained robust suppressive activity after expansion. In contrast, cell lines derived from CD45RA(-) memory-type CD4(+)CD25(high) T cells lost expression of lymph node homing receptors CCR7 and CD62L, contained interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) as well as IL-10-secreting cells, showed only moderate suppression and, most importantly, did not maintain FOXP3 expression. Based on these unexpected findings, we suggest that isolation and expansion of CD45RA(+) naive CD4(+) CD25(high) T cells is the best strategy for adoptive regulatory T (Treg)-cell therapies.
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