Regulatory CD8+ T cells control autoreactive CD4+ clones in healthy subjects

M. Molteni Ph.D., C. Rossetti Ph.D., R. Scorza M.D. a, L.D. Kohn M.D. b

Group of Applied Biology, DBSF, University of Insubria - Via Dunant 3, 21100 Varese, Italy; a Dep. of Internal Medicine, University of Milano, IRCCS Ospedale Maggiore Via Sforza, 35, 20122 Milano, Italy; b Edison Biotechnology Institute, Ohio University, Konneker Research Labs. The Ridge Athens, Ohio 45701-2979.

AIM In a previous study we obtained, from healthy subjects, several T cell lines specific for the TSH receptor (TSHR) characterized by the presence of CD4+ T cells responsive to the antigen and CD8+ T cells unresponsive to TSHR. Aim of this study was to investigate the role of CD8+ cells in regulating the response of TSHR-specific CD4+ clones. METHODS Different T cell lines specific for the TSHR were cloned. Suppression was tested by adding different CD8+ clones in the proliferation assay of CD4+ clones. Cytotoxicity and transwell experiments were performed, as well as experiments of pre-incubation of CD8+ and CD4+ clones followed by depletion of CD8+ before testing proliferation and IL-2 release. RESULTS A subset of CD8+ clones TCR &alpha&beta+, CD28- was selected and showed suppressive effects on TSHR-pulsed CD4+ clones. Suppression (1) was specific (a CD8+ clone suppressed only a single CD4+ clone and not others with different HLA restrictions), (2) required cell-cell interaction, and (3) was not mediated by cytotoxicity. Pre-incubation of CD8+ and CD4+ clones for 1 or 5 days, followed by depletion of the CD8+ cells from the culture, demonstrated that CD4+ cells were anergic since they showed low response to the antigen and a significant impairment of IL-2 production. COMMENT Our results indicate that one of the mechanisms ensuring peripheral tolerance involve CD8+CD28- cells. A disregulation in the control of autoreactive clones by this subset might be important for the onset of autoimmune thyroid diseases.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Autoimmunity.

This presentation received an honorable mention in our poster contest and was recognized with the Symposium Presidents' Award for Scientific Excellence.