Abstract
The existence of cytotoxic T cells (CTL) cross-reacting with the human major histocompatibility antigens HLA-B14 and HLA-B27 suggests that their alloreactivity could be due to presentation of shared peptides in similar binding modes by these molecules. We therefore determined the crystal structures of the subtypes HLA-B*1402, HLA-B*2705, and HLA-B*2709 in complex with a proven self-ligand, pCatA (peptide with the sequence IRAAPPPLF derived from cathepsin A (residues 2-10)), and of HLA-B*1402 in complex with a viral peptide, pLMP2 (RRRWRRLTV, derived from latent membrane protein 2 (residues 236-244) of Epstein-Barr virus). Despite the exchange of 18 residues within the binding grooves of HLA-B*1402 and HLA-B*2705 or HLA-B*2709, the pCatA peptide is presented in nearly identical conformations. However, pLMP2 is displayed by HLA-B*1402 in a conformation distinct from those previously found in the two HLA-B27 subtypes. In addition, the complexes of HLA-B*1402 with the two peptides reveal a nonstandard, tetragonal mode of the peptide N terminus anchoring in the binding groove because of the exchange of the common Tyr-171 by His-171 of the HLA-B*1402 heavy chain. This exchange appears also responsible for reduced stability of HLA-B14-peptide complexes in vivo and slow assembly in vitro. The studies with the pCatA peptide uncover that CTL cross-reactive between HLA-B14 and HLA-B27 might primarily recognize the common structural features of the bound peptide, thus neglecting amino acid replacements within the rim of the binding grooves. In contrast, structural alterations between the three complexes with the pLMP2 peptide indicate how heavy chain polymorphisms can influence peptide display and prevent CTL cross-reactivity between HLA-B14 and HLA-B27 antigens.
Highlights
Tel.: 49-30-450-564731; Fax: 49-30-450-564920; E-mail: andreas.ziegler@charite.de. 2 The abbreviations used are: MHC, major histocompatibility complex; AS, ankylosing spondylitis; CTL, cytotoxic T lymphocytes; HC, heavy chain; of the same species, termed alloreactive T cells, may constitute up to 10% of the T cell pool of an individual, and their precursor frequency can be 100 –1,000-fold higher than that of self-restricted T cells directed against a foreign peptide [1, 2]
Donor cells expressing MHC molecules are directly recognized by host T cells [7], whereas indirect allorecognition involves the presentation of peptides derived from donor proteins by MHC molecules of the host, followed by the detection of the complexes by the host T cells [8]
One of the most important questions regards the individual contribution of the bound peptide and binding groove residues of the heavy chain (HC) of MHC class I antigens to the interaction with T cell receptors (TCR)
Summary
Reconstitution of the HLA-B14 and HLA-B27 Complexes in Vitro—Reconstitution of the HLA-B14 complexes required a much longer time than in the case of the HLA-B27 complexes. The yield of reconstitution of the B*14021⁄7pCatA complex was about 30 times lower than that of the B*27091⁄7pCatA molecule. The yields following reconstitution of B*1402 complexes were Ͼ10 times lower than the yields obtained after refolding the HLA-B27 complexes. The complexes of B*2705 and B*2709 with pLMP2 crystallized in the monoclinic space group P21 as well, albeit under different crystallization conditions, and their crystals contained one molecule per asymmetric unit [24]. The peptide-binding grooves of B*1402 and B*2705 differ from each other at 18 positions (Fig. 1) These amino acid exchanges influence at least three features as follows: the general shape of the binding grooves, the interactions of several pocket-forming residues with atoms of the peptide, and the potential of residues of the ␣1- and ␣2-helices to interact with cell surface-expressed receptor molecules on effector cells. The overall structures of the HC and 2m of all TABLE 1 Data collection and refinement statistics
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