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Attenuating Regulatory T Cell Induction by TLR Agonists through Inhibition of p38 MAPK Signaling in Dendritic Cells Enhances Their Efficacy as Vaccine Adjuvants and Cancer Immunotherapeutics¹

Andrew G. Jarnicki^*, Helen Conroy^*, Corinna Brereton^*, Graham Donnelly^2,*, Deirdre Toomey^*, Kevin Walsh^*, Cheryl Sweeney^*, Olive Leavy^3,*, Jean Fletcher^*, Ed C. Lavelle, Padraic Dunne^* and Kingston H. G. Mills^4,*

^* Immune Regulation Research Group and Adjuvant Research Group, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland

TLR ligands are potent adjuvants and promote Th1 responses to coadministered Ags by inducing innate IL-12 production. We found that TLR ligands also promote the induction of IL-10-secreting regulatory T (Treg) cells through p38 MAPK-induced IL-10 production by dendritic cells (DC). Inhibition of p38 suppressed TLR-induced IL-10 and PGE₂ and enhanced IL-12 production in DC. Incubation of Ag-pulsed CpG-stimulated DC with a p38 inhibitor suppressed their ability to generate Treg cells, while enhancing induction of Th1 cells. In addition, inhibition of p38 enhanced the antitumor therapeutic efficacy of DC pulsed with Ag and CpG and this was associated with an enhanced frequency of IFN--secreting T cells and a reduction of Foxp3⁺ Treg cells infiltrating the tumors. Furthermore, addition of a p38 inhibitor to a pertussis vaccine formulated with CpG enhanced its protective efficacy in a murine respiratory challenge model. These data demonstrate that the adjuvant activity of TLR agonists is compromised by coinduction of Treg cells, but this can be overcome by inhibiting p38 signaling in DC. Our findings suggest that p38 is an important therapeutic target and provides a mechanism to enhance the efficacy of TLR agonists as vaccine adjuvants and cancer immunotherapeutics.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Science Foundation Ireland.

² Current address: Opsona Therapeutics Ltd., St James’s Hospital, Dublin 8, Ireland.

³ Current address: Nature Reviews Immunology, 4–6 Crinan Street, London N1 9XW, U.K.

⁴ Address correspondence and reprint requests to Prof. Kingston H. G. Mills, School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland. E-mail: kingston.mills{at}tcd.ie

⁵ Abbreviations used in this paper: Treg, regulatory T; DC, dendritic cell; Tg, transgenic; CT, cholera toxin; Pa, acellular pertussis vaccine; Pw, whole-cell pertussis vaccine; KLH, keyhole limpet hemocyanin; ODN, oligodeoxynucleotide; LN, lymph node; Pam₃CSK₄, palmitoyl-3-cysteine-serine-lysine-4; COX-2, cyclooxygenase 2.

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