Divergent T-cell receptor recognition modes of a HLA-I restricted extended tumour-associated peptide

Human leukocyte antigen (HLA)-I molecules generally bind short peptides (8-10 amino acids), although extended HLA-I restricted peptides (>10 amino acids) can be presented to T cells. However, the function of such extended HLA-I epitopes in tumour immunity, and how they would be recognised by T-cell receptors (TCR) remains unclear. Here we show that the structures of two distinct TCRs (TRAV4+TRAJ21+-TRBV28+TRBJ2-3+ and TRAV4 + TRAJ8+-TRBV9+TRBJ2-1+), originating from a polyclonal T-cell repertoire, bind to HLA-B*07:02, presenting a 13-amino-acid-long tumour-associated peptide, NY-ESO-160-72. Comparison of the structures reveals that the two TCRs differentially binds NY-ESO-160-72-HLA-B*07:02 complex, and induces differing extent of conformational change of the NY-ESO-160-72 epitope. Accordingly, polyclonal TCR usage towards an extended HLA-I restricted tumour epitope translates to differing TCR recognition modes, whereby extensive flexibility at the TCR-pHLA-I interface engenders recognition

A novel HLA-B18 restricted CD8+ T cell epitope is efficiently cross-presented by dendritic cells from soluble tumor antigen

NY-ESO-1 has been a major target of many immunotherapy trials because it is expressed by various cancers and is highly immunogenic. In this study, we have identified a novel HLA-B*1801-restricted CD8<sup>+</sup>T cell epitope, NY-ESO-1<sub>88–96</sub> (LEFYLAMPF) and compared its direct- and cross-presentation to that of the reported NY-ESO-1<sub>157–165</sub> epitope restricted to HLA-A*0201. Although both epitopes were readily cross-presented by DCs exposed to various forms of full-length NY-ESO-1 antigen, remarkably NY-ESO-1<sub>88–96</sub> is much more efficiently cross-presented from the soluble form, than NY-ESO-1<sub>157–165</sub>. On the other hand, NY-ESO-1<sub>157–165</sub> is efficiently presented by NY-ESO-1-expressing tumor cells and its presentation was not enhanced by IFN-γ treatment, which induced immunoproteasome as demonstrated by Western blots and functionally a decreased presentation of Melan A<sub>26–35</sub>; whereas NY-ESO-1<sub>88–96</sub> was very inefficiently presented by the same tumor cell lines, except for one that expressed high level of immunoproteasome. It was only presented when the tumor cells were first IFN-γ treated, followed by infection with recombinant vaccinia virus encoding NY-ESO-1, which dramatically increased NY-ESO-1 expression. These data indicate that the presentation of NY-ESO-1<sub>88–96</sub> is immunoproteasome dependent. Furthermore, a survey was conducted on multiple samples collected from HLA-B18+ melanoma patients. Surprisingly, all the detectable responses to NY-ESO-1<sub>88–96</sub> from patients, including those who received NY-ESO-1 ISCOMATRIX™ vaccine were induced spontaneously. Taken together, these results imply that some epitopes can be inefficiently presented by tumor cells although the corresponding CD8<sup>+</sup>T cell responses are efficiently primed in vivo by DCs cross-presenting these epitopes. The potential implications for cancer vaccine strategies are further discussed

Pathogenesis, humoral immune responses and transmission between co-housed animals in a ferret model of human RSV infection

Small animal models have been used to obtain many insights regarding the pathogenesis and immune responses induced following infection with human respiratory syncytial virus (hRSV). Amongst those described to date, infections in cotton rats, mice, guinea pigs, chinchillas and Syrian hamsters with hRSV strains Long and/or A2 have been well characterised, although clinical isolates have also been examined. Ferrets are also susceptible to hRSV infection but the pathogenesis and immune responses elicited following infection have not been well characterised. Herein, we describe the infection of adult ferrets with hRSV Long or A2 via the intranasal route and characterised virus replication, as well as cytokine induction, in the upper and lower airways. Virus replication and cytokine induction during the acute phase of infection (days 0-15 post-infection) were similar between the two strains and both elicited high levels of F glycoprotein-specific binding and neutralising antibodies following virus clearance (days 16-22 post-infection). Importantly, we demonstrate transmission from experimentally infected donor ferrets to co-housed naïve recipients and have characterised virus replication and cytokine induction in the upper airways of infected contact animals. Together, these studies provide a direct comparison of the pathogenesis of hRSV Long and A2 in ferrets and highlight the potential of this animal model to study serological responses and examine interventions that limit transmission of hRSV.IMPORTANCE Ferrets have been widely used to study pathogenesis, immunity and transmission following human influenza virus infections, however far less is known regarding the utility of the ferret model to study hRSV infections. Following intranasal (IN) infection of adult ferrets with the well characterised Long or A2 strains of hRSV, we report virus replication and cytokine induction in the upper and lower airways, as well as the development of virus-specific humoral responses. Importantly, we demonstrate transmission of hRSV from experimentally infected donor ferrets to co-housed naïve recipients. Together, these findings significantly enhance our understanding of the utility of the ferret as a small animal model to investigate aspects of hRSV pathogenesis and immunity

Women with endometriosis have higher comorbidities: Analysis of domestic data in Taiwan

AbstractEndometriosis, defined by the presence of viable extrauterine endometrial glands and stroma, can grow or bleed cyclically, and possesses characteristics including a destructive, invasive, and metastatic nature. Since endometriosis may result in pelvic inflammation, adhesion, chronic pain, and infertility, and can progress to biologically malignant tumors, it is a long-term major health issue in women of reproductive age. In this review, we analyze the Taiwan domestic research addressing associations between endometriosis and other diseases. Concerning malignant tumors, we identified four studies on the links between endometriosis and ovarian cancer, one on breast cancer, two on endometrial cancer, one on colorectal cancer, and one on other malignancies, as well as one on associations between endometriosis and irritable bowel syndrome, one on links with migraine headache, three on links with pelvic inflammatory diseases, four on links with infertility, four on links with obesity, four on links with chronic liver disease, four on links with rheumatoid arthritis, four on links with chronic renal disease, five on links with diabetes mellitus, and five on links with cardiovascular diseases (hypertension, hyperlipidemia, etc.). The data available to date support that women with endometriosis might be at risk of some chronic illnesses and certain malignancies, although we consider the evidence for some comorbidities to be of low quality, for example, the association between colon cancer and adenomyosis/endometriosis. We still believe that the risk of comorbidity might be higher in women with endometriosis than that we supposed before. More research is needed to determine whether women with endometriosis are really at risk of these comorbidities

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Structural basis for polyclonal T-cell receptor recognition of a 13 mer peptide from tumour antigen NY-ESO-1 presented by HLA-B*0702

© 2014 Dr. Kok Fei ChanCellular immunity plays a central role in mediating clearance of many varied diseases. The CD8+ T-cell (TCD8+) is an important subset of T-cells which has been implicated to mediate killing of tumour cells. TCD8+ recognise antigenic peptide presented by major histocompatibility complex class I (MHC-I). Because of the closed ends of MHC-I molecules, the presented peptides are usually 8 to 10 amino acid (aa) in length. However, a growing number of studies have shown that peptide longer than 10 aa can be presented for TCD8+ recognition and is equally capable of eliciting potent TCD8+ responses as peptides of canonical length. The long peptides were also frequently observed to form a prominent central bulge when presented by MHC-I molecule, as determined from the solved crystal structures. Such bulged peptide/MHC-I (pMHC-I) conformation poses great challenge for T-cell receptor (TCR) binding, thus results in predominantly biased TCR repertoire. Some TCRs were observed to perch on a rigid bulged pMHC-I, but others were shown to deform the bulged pMHC-I and created a flatter conformation. To date, no study has described that such TCR docking modes could simultaneously use by distinct TCRs recognising the same bulged pMHC-I. We previously reported an immunodominant 13 mer NY-ESO-160-72 peptide derived from cancer-testis antigen NY-ESO-1. This peptide is restricted to HLA-B*0702 and is naturally presented by melanoma cells. Although it adopts a super-bulge in the centre when complexed to HLA-B*0702, unlike other reported cases, TCD8+ responses to the NY-ESO-160-72/HLA-B*0702 is not only immunodominant but also involves diverse TCR repertoire, at least 10 different Vβ families. To understand such unique TCR/pMHC-I interaction, here I used four NY-ESO-160-72-specific TCD8+ clones (KFJ-4, KFJ-5, KFJ-15 and KFJ-37) derived from a melanoma patient vaccinated with NY-ESO-1/ISCOMATRIXTM. The TCR complementarity-determining region (CDR) in these distinct TCD8+ clones were shown to possess unique sequences with different lengths and no conserved CDR3 aa motifs. Further, these TCD8+ clones were demonstrated to recognise naturally presented NY-ESO-160-72/HLA-B*0702 on melanoma cells and have different fine specificities when probed by a series of single aa substituted NY-ESO-160-72 peptides. Different biological requirements for NY-ESO-160-72/HLA-B*0702 recognition were also established: low avidity TCD8+ clone such as the KFJ-15 has higher dependency on CD8 co-receptor for antigen recognition and was less sensitive to melanoma cells than the other TCD8+ clones. The crystal structures for the KFJ-5 TCR and KFJ-37 TCR/NY-ESO-160-72/HLA-B*0702 complexes were solved to 2.0 Å and 2.6 Å resolution, respectively. The structures showed that the NY-ESO-160-72 peptide molded around TCR when approached by distinct TCRs. Consequently, two different NY-ESO-160-72/HLA-B*0702 conformers were described: a deformed ‘helical’ (KFJ-5 TCR) and a ‘super-bulged’ (KFJ-37 TCR). Therefore, polyclonal TCR recognition of the NY-ESO-160-72/HLA-B*0702 is explained by the flexible arrangements of the presented peptide. A diagonal TCR docking orientation was shown to be the optimal binding geometry for such interaction. Notably, the KFJ-5 is an ‘α-centric’ TCR displaying an unusually large α chain contribution (~75% BSA) to interact with the NY-ESO-160-72/HLA-B*0702 when compared to the KFJ-37 TCR α chain (~44% BSA). Moreover, a substantial conformational change was also required for the KFJ-5 TCR CDR3α loop before docking onto the NY-ESO-160-72/HLA-B*0702. This implies that flexibilities at the TCR/pMHC-I interaction interface may play a dominant role for unusual ligand recognition. Our findings represent a novel mechanism, whereby an unusually long peptide could select a diverse TCR repertoire for antigen recognition. Collectively, knowledge acquired from this study has strengthened current understanding on TCR/pMHC-I interaction and may have important implications for rational vaccine design