Multiple sclerosis: Comparison of the human T-cell response to S100β and myelin basic protein reveals parallels to rat experimental autoimmune panencephalitis

Abstract

The adoptive transfer of autoreactive S100β-specific T cells induces experimental autoimmune panencephalomyelitis and uveoretinitis in the Lewis rat, mimicking the distribution of lesions seen in a subset of patients with multiple sclerosis. We studied the frequency and functional properties of the human T-cell response to S100β in eight patients (two relapsing-remitting multiple sclerosis, one chronic-progressive multiple sclerosis, two with multiple sclerosis and uveitis, two neuromyelitis optica, one panuveitis) and in seven healthy individuals, using bovine S100β for T-cell stimulation. Both in patients and controls, the frequency of S100β-specific T-cell responses was half of that obtained for myelin basic protein (MBP), and only 10% of that obtained using purified protein derivative (PPD). The stimulation indices obtained in response to S100β were also less than half those obtained with either MBP or PPD. However, four long-term S100β-specific T-cell lines were established and studied in more detail. The four T-cell lines all exhibited a CD4+, CD8-, T-cell receptor αβ+ surface phenotype and secreted tumour necrosis factor-α, interferon-γ, interleukin-10 and interleukin-4 upon antigenic stimulation, but they were heterogenous with respect to T-cell receptor usage; two T-cell lines expressed Vβ2, one Vβ6.7 and one Vβ 13. Antigen-specificity was confirmed using bovine S100ββ and αβ-isoforms, as well as a recombinant rat S100β preparation. The response to S100β was shown to be HLA-(human leukocyte antigen-) DR-restricted for two of the S100β-specific T-cell lines. Human S100β-specific T-cell lines were cytotoxic, although to a lesser extent than MBP-specific T-cell lines derived from the same donors. The phenotypic and functional properties of human S100β-specific T-cell lines raise the possibility that these T cells are pathogenic, as they are in the rat. The low frequency and proliferative index of S100β-specific, as opposed to MBP-specific T-cell responses suggests that the T-cell response to this widely expressed calcium-binding protein is under more efficient regulatory control.