IL-10 and TGF-β induce alloreactive CD4+CD25- T cells to acquire regulatory cell function

Zong ming Chen, Matthew J. O'Shaughnessy, Irene Gramaglia, Angela Panoskaltsis-Mortari, William J. Murphy, Satwant Narula, Maria G. Roncarolo, Bruce R. Blazar

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152 Scopus citations


We previously reported that interleukin-10 (IL-10) and transforming growth factor (TGF)-β treatment of primary mixed lymphocyte reaction (MLR) cultures resulted in secondary alloantigen-specific hyporesponsiveness and protection from graft-versus-host disease (GVHD) lethality. Here, we report that CD4+ T cells recovered from the IL-10- and TGF-β-treated primary MLR cultures have immunoregulatory function. Tolerized cells significantly inhibited proliferation of naive alloreactive CD4+ T cells in a primary MLR. Inhibition of the naive alloresponse was observed with as few as 1 tolerized cell to 10 naive responder cells. Tolerized cells were able to significantly reduce GVHD lethality when injected with naive alloreactive CD4+ T cells into major histocombatibility class (MHC) II disparate recipients. Rigorous CD25 depletion of the primary MLR had no effect on generation of a regulatory capacity, suggesting that the regulatory cells likely originated from CD4+CD25- T cells. Immune suppression was mediated independently of IL-10 and TGF-β production, as neutralizing antibodies for IL-10, IL-10R, and TGF-β were unable to revert suppression, and IL-10-deficient D4+ T cells were able to mediate in vitro and in vivo suppression. The generation of immunoregulatory cells from a CD4+CD25- population during tolerization with IL-10 and TGF-β provides an additional mechanism to prevent GVHD lethality by T cells that may escape full tolerance induction.

Original languageEnglish (US)
Pages (from-to)5076-5083
Number of pages8
Issue number12
StatePublished - Jun 15 2003

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    Chen, Z. M., O'Shaughnessy, M. J., Gramaglia, I., Panoskaltsis-Mortari, A., Murphy, W. J., Narula, S., Roncarolo, M. G., & Blazar, B. R. (2003). IL-10 and TGF-β induce alloreactive CD4+CD25- T cells to acquire regulatory cell function. Blood, 101(12), 5076-5083.