Recognition of human T-leukemia virus (HTLV-1) envelope by human CD4+ T- cell lines from HTLV-1 seronegative individuals: specificity and clonal heterogeneity

Abstract

Because T-helper cells are critical for immune responses in retroviral infections, CD4+ T-cell lines specific for the human T-leukemia virus type 1 (HTLV-1) envelope have been generated from peripheral T lymphocytes of nonimmune donors to study their naive repertoire. Recombinant fragments (RE1, amino acids [aa] 26–200; RE3, aa 165–307; RE5, aa 308–401; and RE6, aa 165–401) of HTLV-1 envelope, whole envelope glycoprotein, and synthetic peptides were used to induce T- cell lines. CD4+ T-cell lines specific for one or more fragments were obtained from seven of eight individuals tested. T-cell lines generated against envelope glycoprotein from five of five donors did not cross- react with the RE fragments and vice versa. The lines specific for RE and env were mapped with overlapping peptides. The lines with single peptide (narrow) specificity contained a variety of clones that used different T-cell receptor V beta genes. These data (1) suggest that most of the normal individuals carry T-helper precursors specific for epitopes on HTLV-1 envelope; (2) indicate that heterogeneity of HTLV-1 envelope-specific T cells can be detected in the naive repertoire; and (3) define optimal antigenic preparations to be used to assess cellular immunity in HTLV-1-infected individuals.

Human T leukaemia virus type 1 (HTLV‐1) specific T‐helper cell response: clonal fluctuations and repertoire heterogeneity

“…The fact we report here that different clones are specific for an immunodominant peptide of a retroviral antigen matches with previous findings with T-cell clones specific for HIV gp120 (Manca et al, 1991(Manca et al, , 1995b and HIV reverse transcriptase p66 (Manca et al, 1995a). This also supports the concept that dominance is due to processing events favouring the accumulation and cell surface presentation of peptides that associate preferentially with MHC molecules , rather than to lack of specific precursor clones in the Th cell repertoire.…”

“…The breadth of the human repertoire specific for HTLV-1 env is further supported by the observation that clones using the same V gene family are in fact unrelated according to VDJ sequence. This observation is similar to the case of HIV p66-specific T-cell clones (Manca et al, 1995a) and indicates that they spring from distinct precursors which have undergone different combinatorial events during the generation of clonotypic diversity. Similar experiments with HTLV-1infected individuals are currently in progress.…”

“…has already been described with CD8 cells from peripheral blood of HIV-infected individuals examined for V gene usage at different time intervals, with a possible association between limited clonal heterogeneity and disease progression (Pantaleo et al, 1994). The availability of a clonally heterogenous repertoire (Manca et al, 1991(Manca et al, , 1993(Manca et al, , 1995a may be a positive feature of the immune response to retroviruses, and should be exploited by appropriate vaccination protocols aimed at triggering the broad repertoire. On the other hand, if the different Th clones we can identify have different functional features (e.g.…”

“…More details on these lines have been given in a previous report (Manca et al, 1995c). As we have observed with other retroviral antigens (Manca et al, 1991(Manca et al, , 1993(Manca et al, , 1995a, the in vitro Th cell response of naive individuals to HTLV-1 env focuses on limited (immunodominant) regions of the protein, identified when overlapping peptides are used to screen the lines for fine specificity. Certain lines respond to protein antigens, but not to any synthetic peptides.…”

Epitope focus, clonal composition and Th1 phenotype of the human CD4 response to the secretory mycobacterial antigen Ag85

“…This discrepancy between recognition of an epitope in the context of a peptide or in the context of a protein has been described using retroviral antigens [15]. This may impose limitations upon the use of peptides removed from their original context for immunization and must be considered when peptides are inserted in recombinant carriers [20].…”