Is the exquisite specificity of lymphocytes generated by thymic selection or due to evolution?

We have previously argued that the antigen receptors of T and B lymphocytes evolved to be sufficiently specific to avoid massive deletion of clonotypes by negative selection. Their optimal 'specificity' level, i.e.

Role of T cells in severe COVID-19 disease, protection, and long term immunity.

Infection with SARS-CoV-2 causes wide range of disease severities from asymptomatic to life-threatening disease. Understanding the contribution of immunological traits in immunity against SARS-CoV-2 and in protection against severe COVID-19 could result in effective measures to prevent development of severe disease. While the role of cytokines and antibodies has been thoroughly studied, this is not the case for T cells.

Evolution of SARS-CoV-2-specific CD4 T cell epitopes.

Vaccination clearly decreases coronavirus disease 2019 (COVID-19) mortality; however, they also impose selection pressure on the virus, which promotes the evolution of immune escape variants. For example, despite the high vaccination level in especially Western countries, the Omicron variant caused millions of breakthrough infections, suggesting that the highly mutated spike protein in the Omicron variant can escape antibody immunity much more efficiently than the other variants of concern (VOCs). In this study, we investigated the resistance/susceptibility of T helper cell responses that are necessary for generating efficient long-lasting antibody immunity, in several VOCs.

Quantifying the Impact of Human Leukocyte Antigen on the Human Gut Microbiota.

The composition of the gut microbiota is affected by a number of factors, including the innate and adaptive immune system. The major histocompatibility complex (MHC), or the human leukocyte antigen (HLA) in humans, performs an essential role in vertebrate immunity and is very polymorphic in different populations. HLA determines the specificity of T lymphocyte and natural killer (NK) cell responses, including those against the commensal bacteria present in the human gut.

CD200R1L is a functional evolutionary conserved activating receptor in human neutrophils.

Inhibitory and activating immune receptors play a key role in modulating the amplitude and duration of immune responses during infection and in maintaining immune balance in homeostatic conditions. The CD200 Receptor (CD200R) gene family in humans encodes one inhibitory receptor, CD200R1, and one putative activating member, CD200R1 Like (CD200R1L). It is demonstrated that CD200R1L is endogenously expressed by human neutrophils and activates cellular functions such as reactive oxygen species (ROS) production via Syk, PI3Kβ, PI3Kδ, and Rac GTPase signaling.

Identification of a novel conserved signaling motif in CD200 receptor required for its inhibitory function.

The inhibitory signaling of CD200 receptor 1 (CD200R) has been attributed to its NPxY signaling motif. However, NPxY-motifs are present in multiple protein families and are mostly known to mediate protein trafficking between subcellular locations rather than signaling. Therefore, we investigated whether additional motifs specify the inhibitory function of CD200R.

Is T Cell Negative Selection a Learning Algorithm?

Our immune system can destroy most cells in our body, an ability that needs to be tightly controlled. To prevent autoimmunity, the thymic medulla exposes developing T cells to normal "self" peptides and prevents any responders from entering the bloodstream. However, a substantial number of self-reactive T cells nevertheless reaches the periphery, implying that T cells do not encounter all self peptides during this negative selection process.

Revealing factors determining immunodominant responses against dominant epitopes.

Upon recognition of peptide-MHC complexes by T cell receptors (TCR), the cognate T cells expand and differentiate into effector T cells to generate protective immunity. Despite the fact that any immune response generates a diverse set of TCR clones against a particular epitope, only a few clones are highly expanded in any immune response. Previous studies observed that the highest frequency clones usually control viral infections better than subdominant clones, but the reasons for this dominance among T cell clones are still unclear.

VDJdb in 2019: database extension, new analysis infrastructure and a T-cell receptor motif compendium.

Here, we report an update of the VDJdb database with a substantial increase in the number of T-cell receptor (TCR) sequences and their cognate antigens. The update further provides a new database infrastructure featuring two additional analysis modes that facilitate database querying and real-world data analysis. The increased yield of TCR specificity identification methods and the overall increase in the number of studies in the field has allowed us to expand the database more than 5-fold.

Exploratory Study of Predicted Indirectly ReCognizable HLA Epitopes in Mismatched Hematopoietic Cell Transplantations.

HLA-mismatches in hematopoietic stem-cell transplantation are associated with an impaired overall survival (OS). The aim of this study is to explore whether the Predicted Indirectly ReCognizable HLA-Epitopes (PIRCHE) algorithm can be used to identify HLA-mismatches that are related to an impaired transplant outcome. PIRCHE are computationally predicted peptides derived from the patient's mismatched-HLA molecules that can be presented by donor-patient shared HLA.

Immune biomarkers for predicting response to adoptive cell transfer as cancer treatment.

Adoptive cell transfer (ACT) is a form of personalised immunotherapy which has shown promising results in metastasised cancer. For this treatment, autologous T lymphocytes are selected and stimulated in vitro before re-administration in large numbers. However, only a fraction of patients benefit from ACT, and it is not yet known what biomarkers can predict treatment outcome.

VDJdb: a curated database of T-cell receptor sequences with known antigen specificity.

The ability to decode antigen specificities encapsulated in the sequences of rearranged T-cell receptor (TCR) genes is critical for our understanding of the adaptive immune system and promises significant advances in the field of translational medicine. Recent developments in high-throughput sequencing methods (immune repertoire sequencing technology, or RepSeq) and single-cell RNA sequencing technology have allowed us to obtain huge numbers of TCR sequences from donor samples and link them to T-cell phenotypes. However, our ability to annotate these TCR sequences still lags behind, owing to the enormous diversity of the TCR repertoire and the scarcity of available data on T-cell specificities.

Specificity of inhibitory KIRs enables NK cells to detect changes in an altered peptide environment.

The activity of natural killer (NK) cells is tightly regulated by inhibitory and activating receptors. Inhibitory killer immunoglobulin-like receptors (iKIRs) survey the surface of target cells by monitoring the expression of human leukocyte antigen (HLA) class I. The binding of iKIRs has been shown to be sensitive to the peptides presented by HLA class I, implying that iKIRs have the ability to detect the changes in the repertoire of peptide-HLA class I complexes (pHLA), a process occurring during viral infection and in tumor cells.

Long-term adaptation of the influenza A virus by escaping cytotoxic T-cell recognition.

The evolutionary adaptation of the influenza A virus (IAV) to human antibodies is well characterised. Much less is known about the long-term evolution of cytotoxic T lymphocyte (CTL) epitopes, which are important antigens for clearance of infection. We construct an antigenic map of IAVs of all human subtypes using a compendium of 142 confirmed CTL epitopes, and show that IAV evolved gradually in the period 1932-2015, with infrequent antigenic jumps in the H3N2 subtype.

HLA Preferences for Conserved Epitopes: A Potential Mechanism for Hepatitis C Clearance.

Hepatitis C virus (HCV) infections affect more than 170 million people worldwide. Most of these individuals are chronically infected, but some clear the infection rapidly. Host factors seem to play a key role in HCV clearance, among them are the human leukocyte antigen (HLA) class I molecules.

Measles Virus Epitope Presentation by HLA: Novel Insights into Epitope Selection, Dominance, and Microvariation.

Immunity to infections with measles virus (MV) can involve vigorous human leukocyte antigen (HLA) class I-restricted CD8(+) cytotoxic T cell (CTL) responses. MV, albeit regarded monotypic, is known to undergo molecular evolution across its RNA genome. To address which regions of the MV proteome are eligible for recognition by CD8(+) CTLs and how different HLA class I loci contribute to the epitope display, we interrogated the naturally processed and presented MV peptidome extracted from cell lines expressing in total a broad panel of 16 different common HLA-A, -B, and -C molecules.

Predicted Indirectly Recognizable HLA Epitopes Presented by HLA-DRB1 Are Related to HLA Antibody Formation During Pregnancy.

Pregnancy can prime maternal immune responses against inherited paternal HLA of the fetus, leading to the production of child-specific HLA antibodies. We previously demonstrated that donor-specific HLA antibody formation after kidney transplantation is associated with donor-derived HLA epitopes presented by recipient HLA class II (predicted indirectly recognizable HLA epitopes presented by HLA class II [PIRCHE-II]). In the present study, we evaluated the role of PIRCHE-II in child-specific HLA antibody formation during pregnancy.

The evolution of natural killer cell receptors.

Natural killer (NK) cells are immune cells that play a crucial role against viral infections and tumors. To be tolerant against healthy tissue and simultaneously attack infected cells, the activity of NK cells is tightly regulated by a sophisticated array of germline-encoded activating and inhibiting receptors. The best characterized mechanism of NK cell activation is "missing self" detection, i.

Comprehensive Analysis of the Naturally Processed Peptide Repertoire: Differences between HLA-A and B in the Immunopeptidome.

The cytotoxic T cell (CTL) response is determined by the peptide repertoire presented by the HLA class I molecules of an individual. We performed an in-depth analysis of the peptide repertoire presented by a broad panel of common HLA class I molecules on four B lymphoblastoid cell-lines (BLCL). Peptide elution and mass spectrometry analysis were utilised to investigate the number and abundance of self-peptides.

Can Selective MHC Downregulation Explain the Specificity and Genetic Diversity of NK Cell Receptors?

Natural killer (NK) cells express inhibiting receptors (iNKRs), which specifically bind MHC-I molecules on the surface of healthy cells. When the expression of MHC-I on the cell surface decreases, which might occur during certain viral infections and cancer, iNKRs lose inhibiting signals and the infected cells become target for NK cell activation (missing-self detection). Although the detection of MHC-I deficient cells can be achieved by conserved receptor-ligand interactions, several iNKRs are encoded by gene families with a remarkable genetic diversity, containing many haplotypes varying in gene content and allelic polymorphism.

Zooming into the binding groove of HLA molecules: which positions and which substitutions change peptide binding most?

Human leukocyte antigen (HLA) genes are the most polymorphic genes in the human genome. Almost all polymorphic residues are located in the peptide-binding groove, resulting in different peptide-binding preferences. Whether a single amino acid change can alter the peptide-binding repertoire of an HLA molecule has never been shown.

CD8+ TCR Bias and Immunodominance in HIV-1 Infection.

Immunodominance describes a phenomenon whereby the immune system consistently targets only a fraction of the available Ag pool derived from a given pathogen. In the case of CD8(+) T cells, these constrained epitope-targeting patterns are linked to HLA class I expression and determine disease progression. Despite the biological importance of these predetermined response hierarchies, little is known about the factors that control immunodominance in vivo.