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Cognate CD4⁺ Help Elicited by Resting Dendritic Cells Does Not Impair the Induction of Peripheral Tolerance in CD8⁺ T Cells¹

Raymond J. Steptoe^2,*,, Janine M. Ritchie^*, Nicholas S. Wilson, Jose A. Villadangos, Andrew M. Lew^* and Leonard C. Harrison^*

^* Autoimmunity and Transplantation Division and Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; and Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia

Peripheral tolerance is required to prevent autoimmune tissue destruction by self-reactive T cells that escape negative selection in the thymus. One mechanism of peripheral tolerance in CD8⁺ T cells is their activation by resting dendritic cells (DC). In contrast, DC can be "licensed" by CD4⁺ T cells to induce cytotoxic function in CD8⁺ T cells. The question that then arises, whether CD4⁺ T cell help could impair peripheral tolerance induction in self-reactive CD8⁺ T cells, has not been addressed. In this study we show that CD4⁺ T cell activation by resting DC results in helper function that transiently promotes the expansion and differentiation of cognate CD8⁺ T cells. However, both the CD4⁺ and CD8⁺ T cell populations ultimately undergo partial deletion and acquire Ag unresponsiveness, disabling their ability to destroy OVA-expressing pancreatic cells and cause diabetes. Thus, effective peripheral tolerance can be induced by resting DC in the presence of CD4⁺ and CD8⁺ T cells with specificity for the same Ag.

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 These studies were supported by the Juvenile Diabetes Research Foundation, the National Health and Medical Research Foundation of Australia, and the Centre for Immunology and Cancer Research Fellowship.

² Address correspondence and reprint requests to Dr. Raymond J. Steptoe, Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Level 4, R Wing, Building 1, Woolloongabba, Queensland, Australia. E-mail address: rsteptoe{at}cicr.uq.edu.au

³ Abbreviations used in this paper: DC, dendritic cell; int, intermediate; LN, lymph node; MFI, mean fluorescence intensity; RIP, rat insulin promoter; Treg, regulatory T cell.

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