CD4+ T Cell Help Impairs CD8+ T Cell Deletion Induced by Cross-presentation of Self-Antigens and Favors Autoimmunity

Self-antigens expressed in extrathymic tissues such as the pancreas can be transported to draining lymph nodes and presented in a class I–restricted manner by bone marrow-derived antigen-presenting cells. Such cross-presentation of self-antigens leads to CD8⁺ T cell tolerance induction via deletion. In this report, we investigate the influence of CD4⁺ T cell help on this process. Small numbers of autoreactive OVA-specific CD8⁺ T cells were unable to cause diabetes when adoptively transferred into mice expressing ovalbumin in the pancreatic β cells. Coinjection of OVA-specific CD4⁺ helper T cells, however, led to diabetes in a large proportion of mice (68%), suggesting that provision of help favored induction of autoimmunity. Analysis of the fate of CD8⁺ T cells indicated that CD4⁺ T cell help impaired their deletion. These data indicate that control of such help is critical for the maintenance of CD8⁺ T cell tolerance induced by cross-presentation.There is now considerable evidence that CD8⁺ T cell responses can be induced in vivo by professional APCs capable of MHC class I–restricted presentation of exogenous antigens (1–3). This mechanism is known as cross-presentation and was suggested to be instrumental in the immune response to pathogens that avoid professional APCs (2–4). However, if this pathway was only directed towards induction of immunity, cross-presentation of self-antigens to autoreactive CD8⁺ T cells would result in autoimmunity. Recently, in studies using transgenic mice that express a membrane-bound form of OVA under the control of the rat insulin promoter (RIP-mOVA), we have shown that this is not the case. RIP-mOVA mice express membrane-bound OVA in pancreatic islets, kidney proximal tubular cells, thymus and testis. In these mice, OVA was found to enter the class I presentation pathway of a bone marrow– derived cell population and then activate transgenic OVA-specific CD8⁺ T cells (OT-I cells) (3) in LNs draining the sites of antigen expression. Although this form of activation initially led to proliferation of OT-I cells, it ultimately caused their deletion (5). Thus, cross-presentation can remove autoreactive CD8⁺ T cells, and may tolerize the CD8⁺ T cell compartment to self-antigens. These studies, however, did not explain why cross-presentation of a self-antigen induced CD8⁺ T cell tolerance, whereas foreign antigens induced immunity (1–4, 6).In numerous models, CD4⁺ T cell help has been shown to be important for the induction or maintenance of immune responses by CD8⁺ T cells (7–11), but such help is not always essential (12–14). CD4⁺ T cell help has also been shown to be important for avoiding CTL tolerance induction (15–17). In these reports, however, it was not known whether CD8⁺ T cells were activated by cross-presentation or by direct recognition of antigen. Thus, whether CD4⁺ T cell help can affect tolerance induced by cross-presentation has not been addressed. Recently, we demonstrated that cross-priming by foreign antigens requires CD4⁺ T cell help for induction of CTL immunity (6). In this study, we have investigated the influence of such help on the deletion of CD8⁺ T cells induced by cross-presentation of self-antigens.