A dominant Vβ bias in the CTL response after HSV-1 infection is determined by peptide residues predicted to also interact with the TCR β-chain CDR3fn2
Introduction
Cytotoxic T lymphocytes (CTL) recognize a complex of peptide antigen derived from intracellular processing events and products encoded within the major histocompatibility complex (MHC) (Hedrick and Eidelman, 1993). This recognition is mediated by a clonally distributed T cell receptor (TCR) consisting of an αβ-chain heterodimer that has sequence and structural homology to immunoglobulin (Ig) (Chothia et al., 1988; Garboczi et al., 1996; Garcia et al., 1996; Novotny et al., 1986). Both Ig and TCR consist of gene segments encoding variable (V), diversity (D), and joining (J) elements. These elements rearrange and are brought into close proximity with the constant (C) region gene element (Davis and Bjorkman, 1988).The TCR contains regions of hypervariability, similar to Ig, which consist of two V-region encoded loops (termed complementarity determining regions [CDR] 1 and 2) while the CDR3 region is derived from the respective α- and β-chain V-J and V-D-J junctions (Hedrick and Eidelman, 1993).
Many T cell responses are dominated by restricted TCR usage and can range from the repeated inclusion of particular TCR Vβ- and\or Vα-elements, to the preferential usage of both V- and J-elements often in conjunction with conserved V-D-J or V-J junctional sequences. The observed skewing of particular TCR usage in responding T cells can be due to preferential TCR subregion interactions with bacterial or viral superantigens (Acha-Orbea et al., 1991; Kappler et al. 1987a;Kappler et al. 1987b;Pullen et al., 1988; Tripp et al., 1997; White et al., 1989) or due to selection of particular TCR by a specific antigenic peptide\MHC complex (Danska et al., 1990; Hedrick et al., 1988; Jorgensen et al., 1992; Sant Angelo et al., 1996).
Numerous T cell responses have been shown to have antigen-specific sequence conservation located in the junction of the TCR α- and β-chains (Acha-Orbea et al., 1988; Cose et al., 1995; Hedrick et al., 1988; Kelly et al., 1993). A change in an observed junctional conservation is known to directly effect peptide specificity suggesting that this junctional conservation is selected by the peptide component of the peptide\MHC complex (Danska et al., 1990; Engal et al. 1988;Jorgensen et al., 1992; Sant Angelo et al., 1996). Moreover, junctional conservation is often seen together with preferential usage of TCR V-regions which may imply significant TCR contact with the MHC α-helices and can extend to a complete conservation of the complete TCR protein sequence (Aebischer et al., 1990; Burrows et al., 1995; Cibotti et al., 1994; Deckhut et al., 1993;Urban et al., 1988; Winoto et al., 1986). As a consequence the observed TCR bias in a responding T cell repertoire may be due to a combination of both MHC and peptide-antigen selecting T cells with preferred TCR.
TheCD8+ T cell response in C57BL\6 mice after infection with herpes simplex virus type 1 (HSV-1) has been previously characterised with up to 80% of the responding T cells specific for a determinant from HSV-1 glycoprotein B (gB) (Nugent et al., 1994). The gB-specific CTL exhibit a dominant TCR Vβ bias with approximately 60% of the T cells positive for the TCRBV10 element while approximately 20% used the TCRBV8S1 sequence. There is also a further conservation in the gB-specific TCRBV10 population with a conserved tryptophanglycine (WG) doublet found at position 3 and 4 of the CDR3 (Cose et al., 1995). Here we have dissected the ligand components that contribute to the observed V-region bias in the gB-specific response after HSV-1 infection.
Section snippets
Mice, synthetic peptides and cell lines
C57BL\6 mice were purchased from the Central Animal Facility at Monash University. The gB495–502 determinant (SSIEFARL, single letter amino acid code), the position 2 substituted analogue gB-S2I (SIIEFARL), the position 4 substituted analogue gB-E4N (SSINFARL), the position 6 substituted analogue gB-A6E (SSIEFERL) and the position 7 substituted analogue gB-R7K (SSIEFAKL) were synthesised using an Applied Biosystems model 431A synthesiser (ABI, Foster City, CA) and were kindly provided by Dr J.
Immunisation of mice with the gB peptide alone or in the context of an irrelevant protein results in the maintenance of the TCRBV10 bias
Immunisation of C57BL\6 mice with HSV-1 results in the majority of responding T cells specific for the immunodominant determinant gB with approximately 60% of those T cells exhibiting both BV10 and WG junctional sequence conservation in their TCR β-chain. To determine whether the TCBV10 bias seen in C57BL\6 mice was due to the minimal gB determinant, mice were immunised in two ways. The first was to immunise with the minimal gB determinant in adjuvant while the second involved a fusion protein
Discussion
After infection of C57BL\6 mice with HSV-1, the majority of T cells are H-2Kb restricted and are specific for the gB495–502 determinant derived from glycoprotein B (Nugent et al., 1994).Approximately 60% of those gB-specific T cells express a TCRBV10+β-chain that despite the conservation of WG doublet in the CDR3 region show an otherwise diverse CTL response both in terms of TCR α-chain usage and the lack of Jβ-region preference (Cose et al., 1995; Turner et al., 1996).Given that this bias was
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Thiswork was supported by the Australian Research Council, the Australian National Health and Medical Research Council and an Australian Research Council Senior Research Fellowship (to FRC).