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The Journal of Immunology, 2001, 166: 5530-5539.
Copyright © 2001 by The American Association of Immunologists

IFN-{alpha} and IL-10 Induce the Differentiation of Human Type 1 T Regulatory Cells1

Megan K. Levings*, Romina Sangregorio*, Francesca Galbiati*, Stefania Squadrone*, Rene de Waal Malefyt{dagger} and Maria-Grazia Roncarolo2,*

* San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy; and {dagger} DNAX Research Institute, Palo Alto, CA 94304

CD4+ T regulatory type 1 (Tr1) cells suppress Ag-specific immune responses in vitro and in vivo. Although IL-10 is critical for the differentiation of Tr1 cells, the effects of other cytokines on differentiation of naive T cells into Tr1 cells have not been investigated. Here we demonstrate that endogenous or exogenous IL-10 in combination with IFN-{alpha}, but not TGF-{beta}, induces naive CD4+ T cells derived from cord blood to differentiate into Tr1 cells: IL-10+IFN-{gamma}+IL-2-/lowIL-4-. Naive CD4+ T cells derived from peripheral blood require both exogenous IL-10 and IFN-{alpha} for Tr1 cell differentiation. The proliferative responses of the Tr1-containing lymphocyte populations, following activation with anti-CD3 and anti-CD28 mAbs, were reduced. Similarly, cultures containing Tr1 cells displayed reduced responses to alloantigens via a mechanism that was partially mediated by IL-10 and TGF-{beta}. More importantly, Tr1-containing populations strongly suppressed responses of naive T cells to alloantigens. Collectively, these results show that IFN-{alpha} strongly enhances IL-10-induced differentiation of functional Tr1 cells, which represents a first major step in establishing specific culture conditions to generate T regulatory cells for biological and biochemical analysis, and for cellular therapy to induce peripheral tolerance in humans.




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