3FTG

Crystal Structure of H2Db in complex with NP366-N3A variant peptide from influenza

Summary for 3FTG

• Entry DOI: 10.2210/pdb3ftg/pdb
• Descriptor: H-2 class I histocompatibility antigen, D-B alpha chain, Beta-2-microglobulin, NP366-N3A variant peptide from influenza virus, ... (4 entities in total)
• Functional Keywords: h2db, mouse mhc, influenza, immunology, glycoprotein, immune response, membrane, mhc i, transmembrane, immunoglobulin domain, secreted, immune system
• Biological source: Mus musculus (mouse); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01899; Secreted: P01887
• Total number of polymer chains: 3
• Total formula weight: 45419.93

Authors

Gras, S.,Guillonneau, C.,Rossjohn, J. (deposition date: 2009-01-12, release date: 2009-12-29, Last modification date: 2024-10-30)

Primary citation

Valkenburg, S.A.,Gras, S.,Guillonneau, C.,La Gruta, N.L.,Thomas, P.G.,Purcell, A.W.,Rossjohn, J.,Doherty, P.C.,Turner, S.J.,Kedzierska, K.
Protective efficacy of cross-reactive CD8+ T cells recognising mutant viral epitopes depends on peptide-MHC-I structural interactions and T cell activation threshold.
Plos Pathog., 6:e1001039-e1001039, 2010

PubMed Abstract: Emergence of a new influenza strain leads to a rapid global spread of the virus due to minimal antibody immunity. Pre-existing CD8(+) T-cell immunity directed towards conserved internal viral regions can greatly ameliorate the disease. However, mutational escape within the T cell epitopes is a substantial issue for virus control and vaccine design. Although mutations can result in a loss of T cell recognition, some variants generate cross-reactive T cell responses. In this study, we used reverse genetics to modify the influenza NP(336-374) peptide at a partially-solvent exposed residue (N->A, NPN3A mutation) to assess the availability, effectiveness and mechanism underlying influenza-specific cross-reactive T cell responses. The engineered virus induced a diminished CD8(+) T cell response and selected a narrowed T cell receptor (TCR) repertoire within two V beta regions (V beta 8.3 and V beta 9). This can be partially explained by the H-2D(b)NPN3A structure that showed a loss of several contacts between the NPN3A peptide and H-2D(b), including a contact with His155, a position known to play an important role in mediating TCR-pMHC-I interactions. Despite these differences, common cross-reactive TCRs were detected in both the naïve and immune NPN3A-specific TCR repertoires. However, while the NPN3A epitope primes memory T-cells that give an equivalent recall response to the mutant or wild-type (wt) virus, both are markedly lower than wt->wt challenge. Such decreased CD8(+) responses elicited after heterologous challenge resulted in delayed viral clearance from the infected lung. Furthermore, mice first exposed to the wt virus give a poor, low avidity response following secondary infection with the mutant. Thus, the protective efficacy of cross-reactive CD8(+) T cells recognising mutant viral epitopes depend on peptide-MHC-I structural interactions and functional avidity. Our study does not support vaccine strategies that include immunization against commonly selected cross-reactive variants with mutations at partially-solvent exposed residues that have characteristics comparable to NPN3A.

PubMed: 20711359
DOI: 10.1371/journal.ppat.1001039

Experimental method

X-RAY DIFFRACTION (2.6 Å)