Tcr repertoire and influenza12/19/2023 ![]() ![]() Virus-specific CD8 + T cells play a critical role in host defence via the production of antiviral cytokines, the direct killing of virus-infected cells and the establishment of immunological memory. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. SAV is a recipient of the Australian Postgraduate Award. KK and NLG are NHMRC RD Wright Fellows, AWP is a NHMRC Senior Research Fellow, SJT is a Pfizer Senior Research Fellow and CG is a Marie Curie International Fellow and is supported by the 6th FP of the EU, Marie Curie #040840. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: This work was funded by the NHMRC Project Grants to PCD (AI454595) and KK (AI454312), a University of Melbourne Early Career Researcher Grant (to KK), NIH grant AI170251 and NHMRC program grant to PCD, SJT (AI567122). Received: MaAccepted: JPublished: August 12, 2010Ĭopyright: © 2010 Valkenburg et al. Douek, NIH/NIAID, United States of America (2010) Protective Efficacy of Cross-Reactive CD8 + T Cells Recognising Mutant Viral Epitopes Depends on Peptide-MHC-I Structural Interactions and T Cell Activation Threshold. In terms of possible vaccination strategies for rapidly changing viruses or tumours, it appears that priming with cross-reactive mutants that display such characteristics would be of no benefit as the same level of T cell immunity against such mutants can be elicited by exposure to the original virus.Ĭitation: Valkenburg SA, Gras S, Guillonneau C, La Gruta NL, Thomas PG, Purcell AW, et al. This finding results from a markedly lower functional quality and limited structural interactions of the mutant. However, an initial priming with the mutated variant decreases recognition of the original parental virus. We found that established T cell immunity can recognise influenza mutants with variations at positions that are partially involved in T cell recognition. However, influenza viruses mutate to escape the protective immunity. Established T-cell immunity towards conserved viral regions provides some protection against influenza and promotes rapid recovery. Introduction of a new influenza strain into human circulation leads to a rapid global spread of the virus due to minimal antibody immunity. 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. Thus, the protective efficacy of cross-reactive CD8 + T cells recognising mutant viral epitopes depend on peptide-MHC-I structural interactions and functional avidity. Furthermore, mice first exposed to the wt virus give a poor, low avidity response following secondary infection with the mutant. Such decreased CD8 + responses elicited after heterologous challenge resulted in delayed viral clearance from the infected lung. 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. ![]() Despite these differences, common cross-reactive TCRs were detected in both the naïve and immune NPN3A-specific TCR repertoires. This can be partially explained by the H-2D bNPN3A 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. The engineered virus induced a diminished CD8 + T cell response and selected a narrowed T cell receptor (TCR) repertoire within two Vβ regions (Vβ8.3 and Vβ9). 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. Although mutations can result in a loss of T cell recognition, some variants generate cross-reactive T cell responses. However, mutational escape within the T cell epitopes is a substantial issue for virus control and vaccine design. Pre-existing CD8 + T-cell immunity directed towards conserved internal viral regions can greatly ameliorate the disease. Emergence of a new influenza strain leads to a rapid global spread of the virus due to minimal antibody immunity. ![]()
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