State of the art and challenges in sequence based T-cell epitope prediction

Lundegaard et al. Immunome Research 2010, 6(Suppl 2):S3 http://www.immunome-research.com/content/6/S2/S3 IMMUNOME RESEARCH REVIEW Open Access State of the art and challenges in sequence based T-cell epitope prediction Claus Lundegaard1*, Ilka Hoof2, Ole Lund1, Morten Nielsen1 Abstract Sequence based T-cell epitope predictions have improved immensely in the last decade. From predictions of peptide binding to major histocompatibility complex molecules with moderate accuracy, limited allele coverage, and no good estimates of the other events in the antigen-processing pathway, the field has evolved significantly. Methods have now been developed that produce highly accurate binding predictions for many alleles and integrate both proteasomal cleavage and transport events. Moreover have so-called pan-specific methods been developed, which allow for prediction of peptide binding to MHC alleles characterized by limited or no peptide binding data. Most of the developed methods are publicly available, and have proven to be very useful as a shortcut in epitope discovery. Here, we will go through some of the history of sequence-based predictions of helper as well as cytotoxic T cell epitopes. We will focus on some of the most accurate methods and their basic background. Challenges from infectious diseases From the dawn of life, there has been a constant risk of infection by foreign organisms so that only host organisms that have developed an effective protection against these pathogens survived through evolution. On the other hand, this has put an evolutionary pressure on the pathogenic organisms to circumvent the developed protection mechanisms. Especially single-celled organisms and viruses, which generally have a relatively short generation time occasionally combined with a high mutation rate, have succeeded in finding loopholes in the protection. This million-year old arms race has led to the development of a defense system, the immune system, which itself consists of genetically diverse unicellular components that can evolve within the host organism when put under selective pressure. Occasionally, pathogens have evolved that efficiently could infect a specific host organism leading to high mortality. This is typically seen after a change of host [1]. Obviously, too high mortality among the host species would logically also lead to the pathogenic organism’s own end. Due to geographic and biological barriers, such disasters generally hit only locally and were limited to * Correspondence: 1 The Technical University of Denmark - DTU, Dept. of Systems Biology, Center for Biological Sequence Analysis - CBS, Kemitorvet 208, DK-2800 Kgs. Lyngby, Denmark Full list of author information is available at the end of the article neighboring populations, while physically isolated populations avoided infection [2]. Today there are no longer any major restrictions on mobility and contact between human populations, which increases the small but present risk of a new pathogen posing a threat for the existing civilization. Several examples from the past few years have further exposed such threats; the SARS outbreak in 2003 did relatively quickly spread to several continents [3], and a high mortality has been observed in cases where certain strains of the avian flu, Influenza A H5N1 infect humans [4]. The recent Influenza A H1N1 pandemic, originating from pigs, is the latest example of how extensive these infections can be [5,6]. Fortunately, humans have recently been spared from the emergence of new pathogens that are at the same time both very contagious and extremely deadly. Chronic infections, which have little acute mortality but moderate to high mortality in longer terms are another growing problem. Examples of such are infections with hepatitis C virus (HCV), human immunodeficiency virus (HIV), and tuberculosis (TB). The immune system and vaccines The most effective protection against infections is through vaccination. Most vaccines today exist as an inactivated or more harmless form of the pathogenic organism. In several cases, there are problems with either the efficacy, side effects, or that the pathogen is © 2010 Lundegaard et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lundegaard et al. Immunome Research 2010, 6(Suppl 2):S3 http://www.immunome-research.com/content/6/S2/S3 constantly changing and thus escapes the vaccine’s protection. The latter issue is one of the major obstacles to, for instance, a long lasting Influenza A vaccine. Vaccines take advantage of the features of the adaptive immune system. The immune system in general reacts to foreign substances and organisms when discovered in the body. The innate immune system gives a fast and unspecific response, which does not change with repeated occurrences of the same pathogen. The innate immune response might eliminate the intruder by itself but it also signals to the adaptive part of the immune system [7]. An existing effective humoral immunity is an extremely potent way of preventing an actual infection as the intruder will be eliminated immediately. For this reason vaccine development has traditionally been focusing on developing effective antibody responses, which can be obtained using totally inactivated pathogens, parts thereof, or even single proteins in case of vaccines against toxins such as tetanus or diphtheria [8]. However, to obtain strong and long lasting memory it appears that a strong T cell response is often needed [9]. The cellular arm of the immune system consists of two parts; cytotoxic T lymphocytes (CTL), and helper T lymphocytes (HTLs). Both CTL and HTL recognize peptides that are presented on the cell surface to the immune cells by the major histocompatibility complex (MHC) molecule, which in humans is referred to as the Human Leucocyte Antigen (HLA). While HTLs are needed for B cell activation and proliferation to produce antibodies against a given antigen, CTLs perform surveillance of the host cells and recognize and kill infected or malfunctioning cells that present non-self peptides (epitopes) [10]. In a vaccine context, the relevant proteins expressed by a given pathogen are the proteins that will be determining for a good immune response, i.e., the antigens. The part of the antigen that is recognized by the immune system is the epitope, and in the case of both the CTL and the HTL such epitopes consist of small, 8-20 amino acid long polypeptides. CTL epitopes In the MHC class I pathway, peptides from endogenous antigens bound to class I MHCs are presented to CTLs, which are carrying the CD8 receptor (CD8+ T cells). To be presented, a precursor peptide is usually first generated by the proteasome, a large cytosomal protease complex (...truncated)