The data currently available on how the immune system recognises the SARS-CoV-2 virus is growing rapidly. While there are structures of some SARS-CoV-2 proteins in complex with antibodies, which helps us understand how the immune system is able to recognise this new virus; however, we lack data on how T cells are able to recognise this virus. T cells, especially the cytotoxic CD8+ T cells, are critical for viral recognition and clearance. Here we report the X-ray crystallography structure of a T cell receptor, shared among unrelated individuals (public TCR) in complex with a dominant spike-derived CD8+ T cell epitope (YLQ peptide). We show that YLQ activates a polyfunctional CD8+ T cell response in COVID-19 recovered patients. We detail the molecular basis for the shared TCR gene usage observed in HLA-A*02:01+ individuals, providing an understanding of TCR recognition towards a SARS-CoV-2 epitope. Interestingly, the YLQ peptide conformation did not change upon TCR binding, facilitating the high-affinity interaction observed.

Understanding the basis of the immune determinants controlling disease outcome is critical to provide better care to patients and could be exploited for therapeutics and vaccine design. The discovery of the human immunodeficiency virus (HIV) virus as the causing agent of acquired immunodeficiency syndrome (AIDS) decades ago, led to a tremendous amount of research. Among the findings, it was discovered that some rare HIV⁺ individuals, called HIV controllers (HICs), had the ability to control the virus and keep a low viral load without the need of treatment. This ability allows HICs to delay or avoid progression to AIDS. HIV control is strongly associated with the expression of human leukocyte antigen (HLA) alleles in HICs. From the HIV protective HLAs described, HLA-B57 is the most frequent in HIC patients. HLA-B57 can present a large range of highly conserved Gag-derived HIV peptides to CD8⁺ T cells and natural killer (NK) cells, both the focus of this review. So far there are limited differences in the immune response strength, magnitude, or receptor repertoire towards HIV epitopes that could explain viral control in HICs. Interestingly, some studies revealed that during early infection the large breadth of the immune response towards HIV mutants in HLA-B57⁺ HIC patients, might in turn influence the disease outcome.

The SARS-CoV-2 virus responsible for the COVID-19 pandemic has caused significant morbidity and mortality worldwide. With the remarkable advances in medical research, vaccines were developed to prime the human immune system and decrease disease severity. Despite these achievements, the fundamental basis of immunity to the SARS-CoV-2 virus is still largely undefined. Here, we solved the crystal structure of three spike-derived peptides presented by three different HLA molecules, and determined the stability of the overall peptide–HLA complexes formed. The peptide presentation of spike-derived peptides can influence the way in which CD8⁺ T cells can recognise infected cells, clear infection, and therefore, control the outcome of the disease.

HIV controllers can control viral replication and remain healthy, but the mechanism behind this control is unknown. Despite human leukocyte antigen (HLA) diversity in the population, almost 50% of HIV controllers express the HLA-B^∗57:01 molecule, which presents, among others, the Gag-derived epitope TW10. Given TW10's presentation in early infection, TW10-specific T cells could participate in the control of HIV. Here, we study the strength and functionality of TW10-specific T cells from HLA-B^∗57:01⁺/HIV⁺ controller and non-controller individuals. We determine the TW10-specific T cell receptor (TCR) repertoire, revealing a bias in TCR gene usage with the presence of a public TCR. We determine that the T cell response is polyfunctional regardless of the viral load, despite the low affinity of TW10-specific TCRs. We solve the crystal structure of HLA-B^∗57:01-TW10 in complex with a TCR, providing the basis of recognition that underpins the strong TRBV5 bias observed in TW10-specific clonotypes.

The poly(A) tail at the 3′ end of mRNAs determines their stability, translational efficiency, and fate. The shortening of the poly(A) tail, and its efficient removal, triggers the degradation of mRNAs, thus, regulating gene expression. The process is catalyzed by a family of enzymes, known as deadenylases. As the dysregulation of gene expression is a hallmark of cancer, understanding the role of deadenylases has gained additional interest. Herein, the genetic association network shows that CNOT6 and CNOT7 are the most prevalent and most interconnected nodes in the equilibrated diagram. Subsequent silencing and transcriptomic analysis identifies transcripts possibly regulated by specific deadenylases. Furthermore, several gene ontologies are enriched by common deregulated genes. Given the potential concerted action and overlapping functions of deadenylases, we examined the effect of silencing a deadenylase on the remaining ones. Our results suggest that specific deadenylases target unique subsets of mRNAs, whilst at the same time, multiple deadenylases may affect the same mRNAs with overlapping functions.

The influenza B virus (IBV) can pose a significant threat to global health. Despite this, IBV is understudied compared with influenza A virus (IAV). CD8+ T cells have proven highly effective in reducing influenza disease severity. In addition, pre-existing immune responses towards IAV epitopes may provide protection against homologous IBV-derived peptides due to T cell cross-reactivity. To exploit the advantages of T cells for future vaccine developments, a better understanding of the IBV-derived peptide presentation by the highly polymorphic human leukocyte antigen (HLA) is required. We previously determined that the IAV-derived PB1177-A peptide was presented by the HLA-B*18:01 molecule and induced CD8+ T cell responses. Here, we assessed the PB1177-A IBV homologue (PB1177-B). Intracellular cytokine staining assays showed that PB1177-B was unable to activate CD8+ T cells from several HLA-B*18:01+ samples tested. We determined that the IAVand IBV-derived PB1177 adopted different stability and conformation in the cleft of HLA-B*18:01. Molecular dynamics analysis on the crystal structure showed that PB1177-B had a central flexible region with a large hydrophobic patch formed by two phenylalanine residues, not present in PB1177-A. The flexibility and the lower stability of the HLA-B*18:01-PB1177-B complex may hinder CD8+ T cell receptor binding, underpinning the lack of CD8+ T cell activation observed. This provides additional insights into the differences between IAVand IBV-specific CD8+ T cell responses.