Theories and quantification of thymic selection

The peripheral T cell repertoire is sculpted from prototypic T cells in the thymus bearing randomly generated T cell receptors (TCR) and by a series of developmental and selection steps that remove cells that are unresponsive or overly reactive to self-peptide–MHC complexes. The challenge of understanding how the kinetics of T cell development and the statistics of the selection processes combine to provide a diverse but self-tolerant T cell repertoire has invited quantitative modeling approaches, which are reviewed here

Determining the Quantitative Principles of T Cell Response to Antigenic Disparity in Stem Cell Transplantation

Alloreactivity compromising clinical outcomes in stem cell transplantation is observed despite HLA matching of donors and recipients. This has its origin in the variation between the exomes of the two, which provides the basis for minor histocompatibility antigens (mHA). The mHA presented on the HLA class I and II molecules and the ensuing T cell response to these antigens results in graft vs. host disease. In this paper, results of a whole exome sequencing study are presented, with resulting alloreactive polymorphic peptides and their HLA class I and HLA class II (DRB1) binding affinity quantified. Large libraries of potentially alloreactive recipient peptides binding both sets of molecules were identified, with HLA-DRB1 generally presenting a greater number of peptides. These results are used to develop a quantitative framework to understand the immunobiology of transplantation. A tensor-based approach is used to derive the equations needed to determine the alloreactive donor T cell response from the mHA-HLA binding affinity and protein expression data. This approach may be used in future studies to simulate the magnitude of expected donor T cell response and determine the risk for alloreactive complications in HLA matched or mismatched hematopoietic cell and solid organ transplantation

Amino Acid Similarity Accounts for T Cell Cross-Reactivity and for “Holes” in the T Cell Repertoire

Background: Cytotoxic T cell (CTL) cross-reactivity is believed to play a pivotal role in generating immune responses but the extent and mechanisms of CTL cross-reactivity remain largely unknown. Several studies suggest that CTL clones can recognize highly diverse peptides, some sharing no obvious sequence identity. The emerging realization in the field is that T cell receptors (TcR) recognize multiple distinct ligands. Principal Findings: First, we analyzed peptide scans of the HIV epitope SLFNTVATL (SFL9) and found that TCR specificity is position dependent and that biochemically similar amino acid substitutions do not drastically affect recognition. Inspired by this, we developed a general model of TCR peptide recognition using amino acid similarity matrices and found that such a model was able to predict the cross-reactivity of a diverse set of CTL epitopes. With this model, we were able to demonstrate that seemingly distinct T cell epitopes, i.e., ones with low sequence identity, are in fact more biochemically similar than expected. Additionally, an analysis of HIV immunogenicity data with our model showed that CTLs have the tendency to respond mostly to peptides that do not resemble self-antigens. Conclusions: T cell cross-reactivity can thus, to an extent greater than earlier appreciated, be explained by amino acid similarity. The results presented in this paper will help resolving some of the long-lasting discussions in the field of T cel

The dendritic cell algorithm for intrusion detection

As one of the solutions to intrusion detection problems, Artificial Immune Systems (AIS) have shown their advantages. Unlike genetic algorithms, there is no one archetypal AIS, instead there are four major paradigms. Among them, the Dendritic Cell Algorithm (DCA) has produced promising results in various applications. The aim of this chapter is to demonstrate the potential for the DCA as a suitable candidate for intrusion detection problems. We review some of the commonly used AIS paradigms for intrusion detection problems and demonstrate the advantages of one particular algorithm, the DCA. In order to clearly describe the algorithm, the background to its development and a formal definition are given. In addition, improvements to the original DCA are presented and their implications are discussed, including previous work done on an online analysis component with segmentation and ongoing work on automated data preprocessing. Based on preliminary results, both improvements appear to be promising for online anomaly-based intrusion detection.Comment: Bio-Inspired Communications and Networking, IGI Global, 84-102, 201

Down-Regulation of the Interferon Signaling Pathway in T Lymphocytes from Patients with Metastatic Melanoma

BACKGROUND: Dysfunction of the immune system has been documented in many types of cancers. The precise nature and molecular basis of immune dysfunction in the cancer state are not well defined. METHODS AND FINDINGS: To gain insights into the molecular mechanisms of immune dysfunction in cancer, gene expression profiles of pure sorted peripheral blood lymphocytes from 12 patients with melanoma were compared to 12 healthy controls. Of 25 significantly altered genes in T cells and B cells from melanoma patients, 17 are interferon (IFN)-stimulated genes. These microarray findings were further confirmed by quantitative PCR and functional responses to IFNs. The median percentage of lymphocytes that phosphorylate STAT1 in response to interferon-α was significantly reduced (Δ = 16.8%; 95% confidence interval, 0.98% to 33.35%) in melanoma patients (n = 9) compared to healthy controls (n = 9) in Phosflow analysis. The Phosflow results also identified two subgroups of patients with melanoma: IFN-responsive (33%) and low-IFN-response (66%). The defect in IFN signaling in the melanoma patient group as a whole was partially overcome at the level of expression of IFN-stimulated genes by prolonged stimulation with the high concentration of IFN-α that is achievable only in IFN therapy used in melanoma. The lowest responders to IFN-α in the Phosflow assay also showed the lowest gene expression in response to IFN-α. Finally, T cells from low-IFN-response patients exhibited functional abnormalities, including decreased expression of activation markers CD69, CD25, and CD71; T(H)1 cytokines interleukin-2, IFN-γ, and tumor necrosis factor α, and reduced survival following stimulation with anti-CD3/CD28 antibodies compared to controls. CONCLUSIONS: Defects in interferon signaling represent novel, dominant mechanisms of immune dysfunction in cancer. These findings may be used to design therapies to counteract immune dysfunction in melanoma and to improve cancer immunotherapy

Functional Analysis of Immunocompromised Patients’ Leucocytes by Single-cell Mass Cytometry

Immunodeficiencies make up a large group of diseases characterized by heterogeneous clinical manifestations, including life-threatening infections, autoimmunity, chronic inflammation, allergy and malignant diseases. They are classically divided in primary (PID) and secondary (SID) immunodeficiencies and they can be caused by monogenic defects or be secondary to exogenous factors, malignant or non-malignant diseases. In the last 20 years, accelerating progress has been made in identifying new forms of PIDs thanks to the advances of molecular and genetic characterizations. These disorders are either diagnosed early in life or even later, in adults. It is estimated that 1-2% of the population might be affected with any type of the whole PID spectrum. Immune cell characterization, particularly by flow cytometry techniques, has extensively showed its importance in the clinical management of patients presenting immune deficiencies with quantitative cell defects, as well as in the understanding of the immune system. It has already improved the classification of immunological diseases, as well as contributed to improve treatment efficacy and follow-up. Recently, mass cytometry techniques have been used for diagnostic purposes, significantly increasing the breadth and depth of the functional and phenotypic characterization of a patient’s immune cells, in comparison to traditional flow cytometry techniques. These advancements are driven by the great increase in measurable parameters provided by mass cytometry, which allows for all major known immune cell populations and subpopulations to be characterized with a single analysis. The major contribution of this research resides in directly testing the functional activity and response of a patient's immune cells to different stimuli. The highly multiparametric nature of mass cytometry allows for both a broad and in depth characterization of the functional immune response using only a minimal volume of a patient's blood (1 mL) with results available within one day, thus drastically improving time to diagnosis. In addition to having a proportional and phenotypic characterization of a patient's immune cells, identifying the functionally abnormal cell population(s) will provide the clinicians with an even better understanding of their patient's immunological defect. Interpretation of the mass cytometry results along with the patient's clinical data will allow for the identification of signatures associated with specific immunological defects, new classes of immunodeficiencies and therapies that are best adapted to a specific class of an immunological disorder, hence improving the diagnosis and the benefits for immunocompromised patients

Identifying Individual T Cell Receptors of Optimal Avidity for Tumor Antigens.

Cytotoxic T cells recognize, via their T cell receptors (TCRs), small antigenic peptides presented by the major histocompatibility complex (pMHC) on the surface of professional antigen-presenting cells and infected or malignant cells. The efficiency of T cell triggering critically depends on TCR binding to cognate pMHC, i.e., the TCR-pMHC structural avidity. The binding and kinetic attributes of this interaction are key parameters for protective T cell-mediated immunity, with stronger TCR-pMHC interactions conferring superior T cell activation and responsiveness than weaker ones. However, high-avidity TCRs are not always available, particularly among self/tumor antigen-specific T cells, most of which are eliminated by central and peripheral deletion mechanisms. Consequently, systematic assessment of T cell avidity can greatly help distinguishing protective from non-protective T cells. Here, we review novel strategies to assess TCR-pMHC interaction kinetics, enabling the identification of the functionally most-relevant T cells. We also discuss the significance of these technologies in determining which cells within a naturally occurring polyclonal tumor-specific T cell response would offer the best clinical benefit for use in adoptive therapies, with or without T cell engineering