Characterization of the human CD4+ T-cell repertoire specific for major histocompatibility class I-restricted antigens

Abstract

While CD4+ T lymphocytes usually recognize antigens in the context of major histocompatibility (MHC) class II alleles, occurrence of MHC class-I restricted CD4+ T cells has been reported sporadically. Taking advantage of a highly sensitive MHC tetramer-based enrichment approach allowing detection and isolation of scarce Ag-specific T cells, we performed a systematic comparative analysis of HLA-A*0201-restricted CD4+ and CD8+ T-cell lines directed against several immunodominant viral or tumoral antigens. CD4+ T cells directed against every peptide-MHC class I complexes tested were detected in all donors. These cells yielded strong cytotoxic and T helper 1 cytokine responses when incubated with HLA-A2+ target cells carrying the relevant epitopes. HLA-A2-restricted CD4+ T cells were seldom expanded in immune HLA-A2+ donors, suggesting that they are not usually engaged in in vivo immune responses against the corresponding peptide-MHC class I complexes. However, these T cells expressed TCR of very high affinity and were expanded following ex vivo stimulation by relevant tumor cells. Therefore, we describe a versatile and efficient strategy for generation of MHC class-I restricted T helper cells and high affinity TCR that could be used for adoptive T-cell transfer- or TCR gene transfer-based immunotherapies. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.