Human CD4+ T lymphocytes recognize a highly conserved epitope of human T lymphotropic virus type 1 (HTLV-1) env gp21 restricted by HLA DRB1*0101

Abstract

HTLV-1 causes two distinct human diseases, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T cell leukaemia/lymphoma (ATL). Persistently infected individuals carry a risk of <1% of developing either disease. These basic epidemiological data imply that virus-host interactions, especially immunogenetic factors, influence the outcome of infection. Several studies showed that the HLA class II DR1 DQ5 haplotype is over-represented in HAM/TSP, but rare in ATL. Therefore, we selected four patients with HAM/TSP and one seronegative control who all carried the HLA DR1 DQ5 haplotype. We analysed the CD4+ T lymphocyte response against eight synthetic peptides of HTLV-1 envelope (env) glycoprotein gp21, a crucial target antigen in HAM/TSP. The first of two immunodominant epitopes corresponded to a domain of the HTLV-1 envelope protein which had previously been shown to be essential for HTLV-1 envelope function. The second immunodominant epitope overlapped a highly conserved sequence of the retroviral transmembrane envelope protein. DR1 (DRB1*0101)-restricted T lymphocytes were activated by the conserved peptide sequence in nanomolar concentrations. In contrast, this conserved sequence can also induce non-specific, cAMP-mediated immunosuppressive effects on T cells when added in micromolar concentrations to culture media, as shown by Haraguchi S, Good RA, James-Yarish M, Cianciolo GJ, Day NK, Proc Natl Acad Sci USA 1995; 92:5568-71. Hence, HTLV-1 env gp21 might exert either stimulating immunological or immunosuppressive effects in HTLV-1-infected individuals, depending on the level of its expression and the presence of HLA DRB1*0101.

Fig. 1

Inhibition of proliferation by anti-MHC MoAbs. In a representative experiment using T cell line 910/8G7, there was a significant inhibition of antigen-specific proliferation by anti-HLA-DR antibodies (*). Data are expressed as mean + s.d.

Fig. 2

Proliferation of a HTLV-1 gp21 sp378/sp382-specific CD4⁺ T cell line (BK/1C11) depending on concentration and amino acid sequences of peptides. (a) Response to two long overlapping synthetic peptides, sp378 and sp382, which were used for selection of T cell lines, and to recombinant HTLV-1 p21. (b) Epitope analysis using short overlapping synthetic peptides with one amino acid shift. Values are expressed as mean + s.d. of triplicated data per point.

Fig. 3

Analysis of epitope specificity of T cell line BK/2C7 for HTLV-1 gp21 using different overlapping peptides. Only recombinant p21 (rp21), peptides sp400 (amino acids 400–426) and en84 (amino acids 416–430) elicited a strong proliferative response, whereas all other peptides, including peptide sequences 396–410, 401–415, 406–420, 411–425, were negative (for clarity only one negative peptide is shown). Peptide concentrations were 1 μmolll. Data are expressed as mean + s.d.