Skewed association of polyfunctional antigen-specific CD8 T cell populations with HLA-B genotype

Harari, A., Cellerai, C., Enders, F.B., Kostler, J., Codarri, L., Tapia, G., Boyman, O., Castro, E., Gaudieri, S., James, I., John, M., Wagner, R., Mallal, S. and Pantaleo, G. (2007) Skewed association of polyfunctional antigen-specific CD8 T cell populations with HLA-B genotype. Proceedings of the National Academy of Sciences, 104 (41). pp. 16233-16238.

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Abstract

We studied CD8 T cell responses against HIV-1, cytomegalovirus, Epstein-Barr virus, and influenza in 128 subjects and demonstrate that polyfunctional CD8 T cell responses, also including IL-2 production and Ag-specific proliferation, are predominantly driven by virus epitopes restricted by HLA-B alleles. Interestingly, these protective CD8 T cells are equipped with low-avidity T cell receptors (TCRs) for the cognate virus epitope. Conversely, HLA-Arestricted epitopes are mostly associated with "only effector" IFN-γ-secreting, with cytotoxicity, and with the lack of IL-2 production and Ag-specific proliferation. These CD8 T cells are equipped with high-avidity TCR and express higher levels of the T cell exhaustion marker PD-1. Thus, the functional profile of the CD8 T cell response is strongly influenced by the extent to which there is stimulation of polyfunctional (predominantly restricted by HLA-B) versus only effector (restricted by HLA-A) T cell responses. These results provide the rationale for the observed protective role of HLA-B in HIV-1-infection and new insights into the relationship between TCR avidity, PD-1 expression, and the functional profile of CD8 T cells.