Sewell, A. K. | Search bioRxiv

bioRxiv2021

Spatial, temporal and molecular dynamics of swine influenza virus-specific CD8 tissue resident memory T cells.

We defined naive, central memory, effector memory and terminally differentiated porcine CD8 T cells and analyzed their phenotype in lymphoid and respiratory tissues after influenza infection or immunization using peptide-MHC tetramers of three influenza nucleoprotein (NP) epitopes. The hierarchy of response to the three epitopes changes during the response in different tissues. Most NP-specific CD8 T cells in broncho-alveolar lavage (BAL) and lung are tissue resident memory cells (TRM), that express CD69 and have an effector memory or terminally differentiated phenotype. NP-specific cells isolated from BAL express genes characteristic of TRM, but gene expression differs at 7, 21 and 63 days post infection. The frequency of NP-specific cells declines over 63 days in all tissues but is best maintained in BAL. The pig is a powerful model for understanding how best to induce and harness local immunity to respiratory viruses. One sentence summaryInfluenza NP-specific porcine tissue resident memory CD8 T cells persist in the lung with major changes in gene expression.

immunology↗

bioRxiv2020

CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor

CD8+ T cells are inherently cross-reactive and recognize numerous peptide antigens in the context of a given major histocompatibility complex class I (MHCI) molecule via the clonotypically expressed T cell receptor (TCR). The lineally expressed coreceptor CD8 interacts coordinately with MHCI at a distinct and largely invariant site to slow the TCR/peptide-MHCI (pMHCI) dissociation rate and enhance antigen sensitivity. However, this biological effect is not necessarily uniform, and theoretical models suggest that antigen sensitivity can be modulated in a differential manner by CD8. We used an intrinsically controlled system to determine how the relationship between the TCR/pMHCI interaction and the pMHCI/CD8 interaction affects the functional sensitivity of antigen recognition. Our data show that modulation of the pMHCI/CD8 interaction can reorder the agonist hierarchy of peptide ligands across a spectrum of affinities for the TCR. SIGNIFICANCESufficient immune coverage of the peptide universe within a finite host requires highly degenerate T cell receptors (TCRs). However, this inherent need for antigen cross-recognition is associated with a high risk of autoimmunity, which can only be mitigated by a process of adaptable specificity. We describe a mechanism that resolves this conundrum by allowing individual clonotypes to focus on specific peptide ligands without alterations to the structure of the TCR.

immunology↗