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Human CD4⁺ T Cells Displaying Viral Epitopes Elicit a Functional Virus-Specific Memory CD8⁺ T Cell Response¹

Eleni Adamopoulou^2,*, Jan Diekmann^*, Eva Tolosa, Gaby Kuntz^*, Hermann Einsele^*, Hans-Georg Rammensee and Max S. Topp^*

^* Medical Clinic and Polyclinic II, Julius-Maximilian University of Würzburg, Würzburg, Germany; Hertie Institute for Clinical Brain Research, Eberhard-Karls University of Tuebingen, Tuebingen, Germany; and Department of Immunology, Institute for Cell Biology, Eberhard-Karls University of Tuebingen, Tuebingen, Germany

The Ag-specific cellular recall response to herpes virus infections is characterized by a swift recruitment of virus-specific memory T cells. Rapid activation is achieved through formation of the immunological synapse and supramolecular clustering of signal molecules at the site of contact. During the formation of the immunological synapse, epitope-loaded MHC molecules are transferred via trogocytosis from APCs to T cells, enabling the latter to function as Ag-presenting T cells (T-APCs). The contribution of viral epitope expressing T-APCs in the regulation of the herpes virus-specific CD8⁺ T cell memory response remains unclear. Comparison of CD4⁺ T-APCs with professional APCs such as Ag-presenting CD40L-activated B cells (CD40B-APCs) demonstrated reduced levels of costimulatory ligands. Despite the observed differences, CD4⁺ T-APCs are as potent as CD40B-APCs in stimulating herpes virus-specific CD8⁺ T cells resulting in a greater than 35-fold expansion of CD8⁺ T cells specific for dominant and subdominant viral epitopes. Virus-specific CD8⁺ T cells generated by CD4⁺ T-APCs or CD40B-APCs showed both comparable effector function such as specific lysis of targets and cytokine production and also did not differ in their phenotype after expansion. These results indicate that viral epitope presentation by Ag-specific CD4⁺ T cells may contribute to the rapid recruitment of virus-specific memory CD8⁺ T cells during a viral recall response.

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 Grant LSHB-CT-2004-503319 from Allostem and SFB-479/TP-C12 from Deutsche Forschungsgemeinschaft.

² Address correspondence and reprint requests to Eleni Adamopoulou, Medical Clinic and Polyclinic II, Julius-Maximilians University of Würzburg, Röntgernring 11, D-97070 Würzburg, Germany. E-mail address: eleni.adamopoulou{at}mail.uni-wuerzburg.de

³ Abbreviations used in this paper: IS, immunological synapse; ICC, intracellular cytokine; NGFR, nerve growth factor receptor; CD62L, CD62 ligand; T-APC, Ag-presenting T cell; CD40-B, CD40L-activated B cell; CD40B-APC, Ag-presenting CD40-B cell; CsA, cyclosporin A; GALV, gibbon ape leukemia virus; LCL, lymphoblastoid cell line; PGK, phosphoglycerate kinase; Ii, invariant chain; t-CD40L, CD40L-transfected NIH 3T3 cell.