Can Keşmir

Can Keşmir
Utrecht University | UU · Division of Theoretical Biology and Bioinformatics

PhD

About

139
Publications
15,956
Reads
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6,447
Citations
Citations since 2017
14 Research Items
3236 Citations
20172018201920202021202220230100200300400500600
20172018201920202021202220230100200300400500600
20172018201920202021202220230100200300400500600
20172018201920202021202220230100200300400500600
Additional affiliations
December 1999 - present
Utrecht University
February 1999 - August 2005
Technical University of Denmark
Position
  • PostDoc Position
January 1995 - December 2005
Technical University of Denmark

Publications

Publications (139)
Article
Full-text available
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, i...
Article
Full-text available
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...
Article
Full-text available
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 specific...
Article
Full-text available
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 predi...
Article
Full-text available
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...
Conference Paper
p>Over the past years we have learned that the T-cell-based immune system frequently responds to the neoantigens that arise as a consequence of the accumulated DNA damage causing the malignant transformation. Furthermore, recognition of neoantigens appears an important driver of the clinical activity of both T-cell checkpoint blockade and adoptive...
Preprint
Full-text available
The human leukocyte antigen (HLA) is associated with many (infectious) disease outcomes. These associations are perhaps best documented for HIV-1. For example, the HLA-B*58:01 allele is associated with control of the virus, while HLA-B*18:01 is considered detrimental. In HLA disease association studies, it is often ignored that certain HLA molecule...
Article
Full-text available
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...
Article
Aim 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 (PIRCHE-II). I...
Article
Full-text available
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 technolo...
Article
Full-text available
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...
Article
Full-text available
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 N...
Article
Full-text available
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 differ...
Article
Full-text available
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. Certain HLA molecules, e.g., B*27 and B*57, are associa...
Article
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 indirec...
Article
Full-text available
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 ut...
Article
Full-text available
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 (...
Article
Full-text available
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. To experimentally...
Article
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 p...
Article
Full-text available
Natural killer cell receptors (NKRs) monitor the expression of MHC class I and stress molecules to detect unhealthy tissue, such as infected or tumor cells. The NKR gene family shows a remarkable genetic diversity, containing several genes encoding receptors with activating and inhibiting signaling, and varying in gene content and allelic polymorph...
Article
Antibodies against T cell checkpoint molecules have started to revolutionize cancer treatment. Nevertheless, less than half of all patients respond to these immunotherapies. Recent work supports the potential value of biomarkers that predict therapy outcome and inspires the development of assay systems that interrogate other aspects of the cancer-i...
Article
Full-text available
Proteolysis is the general term to describe the process of protein degradation into peptides. Proteasomes are the main actors in cellular proteolysis, and their activity can be measured in in vitro digestion experiments. However, in vivo proteolysis can be different than what is measured in these experiments if other proteases participate or if pro...
Article
Full-text available
Unlabelled: Although CD8(+) T cells are important for the control of HIV-1 in vivo, the precise correlates of immune efficacy remain unclear. In this study, we conducted a comprehensive analysis of viral sequence variation and T-cell receptor (TCR) repertoire composition across multiple epitope specificities in a group of antiretroviral treatment-...
Article
Full-text available
Mucosal-associated invariant T (MAIT) cells express a semi-invariant T cell receptor (TCR) that detects microbial metabolites presented by the nonpolymorphic major histocompatibility complex (MHC)-like molecule MR1. The highly conserved nature of MR1 in conjunction with biased MAIT TCRα chain usage is widely thought to indicate limited ligand prese...
Article
Short-term in vitro expansion of antigen-specific T cells is an appreciated assay for the analysis of small memory T cell populations. However, how well short-term expanded T cells represent the direct ex vivo situation remains to be elucidated. In this study we compared the clonality of Epstein-Barr virus (EBV) and cytomegalovirus (CMV)-specific C...
Article
Full-text available
The responsiveness of natural killer (NK) cells is controlled by balancing signals from activating and inhibitory receptors. The most important ligands of inhibitory NK cell receptors are the highly polymorphic major histocompatibility complex (MHC) class I molecules, which allow NK cells to screen the cellular health of target cells. Although thes...
Article
Full-text available
Different human leukocyte antigen (HLA) haplotypes (i.e., the specific combinations of HLA-A, -B, -DR alleles inherited together from one parent) are observed in different frequencies in human populations. Some haplotypes, like HLA-A1-B8, are very frequent, reaching up to 10% in the Caucasian population, while others are very rare. Numerous studies...
Article
Aim Hematopoietic Stem-Cell Transplantation (HSCT) with an HLA-mismatched donor is a risk factor for Graft-Versus-Host Disease (GVHD). We have recently shown that graft-versus-host reactivity after HSCT with single HLA mismatched adult-unrelated donors is predictable [Thus et al. submitted]. In this setting, the number of peptides derived from the...
Article
This study aimed to evaluate HIV sequence evolution in whole genes and in CD8 T-cell epitope regions following immunotherapy and subsequent analytical treatment interruption (ATI). A second objective of this study was to analyze associations between vaccine-specific immune responses and epitope mutation rates. HIV-1-infected patients on combined an...
Article
Full-text available
Natural killer (NK) cells are circulating lymphocytes that play an important role in the control of viral infections and tumors. Their functions are regulated by several activating and inhibitory receptors. A subset of these receptors in human NK cells are the killer immunoglobulin-like receptors (KIRs), which interact with the highly polymorphic M...
Article
Full-text available
T-cells have to recognize peptides presented on MHC molecules to be activated and elicit their effector functions. Several studies demonstrate that some peptides are more immunogenic than others and therefore more likely to be T-cell epitopes. We set out to determine which properties cause such differences in immunogenicity. To this end, we collect...
Article
Full-text available
The evidence for T-cell–mediated regression of human cancers such as non–small-cell lung carcinoma, renal cell carcinoma, and—in particular—melanoma after immunotherapy is strong. Anti-CTLA4 (ipilimumab) treatment has been approved for treatment of meta-static melanoma,1 and antibody-mediated blockade of PD-1, a second inhibitory receptor on T cell...
Article
9085 Background: Evidence for T cell mediated regression of human cancer in particular melanoma following immunotherapy is strong. Anti-CTLA4 treatment has been approved for treatment of metastatic melanoma and blockade of PD-1 has shown encouraging results. However, it is unknown which T cell reactivities are involved in cancer regression. Reactiv...
Article
Full-text available
CD8(+) T cells recognize infected or dysregulated cells via the clonotypically expressed αβ TCR, which engages Ag in the form of peptide bound to MHC class I (MHC I) on the target cell surface. Previous studies have indicated that a diverse Ag-specific TCR repertoire can be beneficial to the host, yet the determinants of clonotypic diversity are po...
Article
Background: HLA class-I mismatches selectively induce antibody formation after kidney transplantation. The de novo development of donor-specific IgG HLA class-I antibodies may be dependent on the HLA class-II background of the patient by presenting T-helper epitopes within the recognized HLA class-I antigens. Methods: The correlation between ant...
Article
Full-text available
In adults, circulating inflammatory mediators and activated CD14(++) monocytes link obesity to its metabolic and cardiovascular complications. However, it is largely unknown whether these inflammatory changes already occur in childhood obesity. To survey inflammatory changes during the early stages of obesity, we performed a comprehensive analysis...
Data
Hydrophobicity vs. impairment of binding to HLA alleles. Change in hydrophobicity (hydrophobicity of the mutant amino acid minus hydrophobicity of the wild-type amino acid) was correlated with the maximal impairment of binding to both HLA-A and HLA-B alleles (see main text). A significant negative correlation was found for all three measures of hyd...
Data
The table lists all HLA alleles (A and B) used in the analysis. The first row lists the HLA alleles in the four-digit precision. The second row gives their expected frequency in the US population (see also Materials & Methods). (XLS)
Data
Eluted peptides show a significantly higher C-terminal processing probability than other predicted binders. (A) In order to normalize the peptide data sets for predicted binding affinity, for each HLA allotype, we picked an affinity-matched subset of predicted binders so that the range of predicted binding affinities was the same as the range for e...
Data
Distribution of predicted cellular compartments for all human proteins and the source proteins identified for the Johnson data and the Ben Dror data. Subcellular localization as given by WoLF PSORT (nucl = nucleus, mito = mitochondria, extr = extracellular, ER = endoplasmic reticulum, cyto_nucl = cytosol and nucleus, cyto = cytosol, plas = plasma m...
Data
Eluted peptides are more likely to be produced by the immunoproteasome and are more efficiently transported by TAP. The boxplots compare eluted 9mer peptides and predicted binders from the same set of source proteins in terms of (A) predicted C-terminal cleavage probability by the immunoproteasome and (B) predicted TAP transport efficiency. Here, t...
Data
Eluted vaccinia peptides show a significantly higher (A) predicted binding affinity to A*02:01 and B*15:01, respectively, and (B) predicted C-terminal processing probability (for A*02:01-eluted peptides) than other predicted binders from the same set of vaccinia proteins. (TIF)
Data
Comparison of sampled and non-sampled human proteins in terms of protein abundance after normalization for protein length. Normalization was achieved by choosing a random subset of non-sampled proteins that show the same length distribution as the set of sampled proteins. (TIF)
Data
The gene expression level of vaccinia genes is correlated with the sampling state (none, one, or several peptides found by elution). The gene expression level was measured at indicated time points after infection by Assarsson et al. (2008). (TIF)
Article
Full-text available
The peptide repertoire that is presented by the set of HLA class I molecules of an individual is formed by the different players of the antigen processing pathway and the stringent binding environment of the HLA class I molecules. Peptide elution studies have shown that only a subset of the human proteome is sampled by the antigen processing machin...
Article
Full-text available
Human immunodeficiency virus (HIV-1) is, like most pathogens, under selective pressure to escape the immune system of its host. In particular, HIV-1 can avoid recognition by cytotoxic T lymphocytes (CTLs) by altering the binding affinity of viral peptides to human leukocyte antigen (HLA) molecules, the role of which is to present those peptides to...
Article
Full-text available
The cellular immune system screens peptides presented by host cells on MHC molecules to assess if the cells are infected. In this study we examined whether the presented peptides contain enough information for a proper self/nonself assessment by comparing the presented human (self) and bacterial or viral (nonself) peptides on a large number of MHC...
Data
Full-text available
Self/nonself overlaps based on non-anchor positions. For different HLA molecules, the exact self/nonself overlap was determined based on non-anchor positions (P1 and P3–8). The average overlap was 0.4%. (PDF)
Data
Full-text available
The self/nonself overlap of identical and non-identical overlaps versus the binding specificity. The precise overlap of all peptide positions (P1–9, left figure, y-axis), and the degenerate overlap of the T-cell recognized middle positions (P3–8, right figure, y-axis), as well as the fraction of presented self peptides (both figures, x-axis) for ea...