Table of Contents

Volume 2, Issue 2

  April/May/June 2011

  Pages 75 - 124

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PERSPECTIVES

Open Access Article

Cells diversify transmembrane signaling through the controlled chaos of protein disorder

Alexander B. Sigalov
Pages 75 - 79
http://dx.doi.org/10.4161/self.2.2.15756
Abstract | PDF

Cell surface receptors function to transduce signals across the cell membrane leading to a variety of biologic responses. Structurally, these integral proteins can be classified into two main families, depending on whether extracellular ligand-binding and intracellular signaling domains are located on the same protein chain (single-chain receptors, SRs) or on separate subunits (multichain receptors, MRs). Since most MRs are immune receptors, they are all commonly referred to as multichain immune recognition receptors (MIRRs). Recent studies reveal that, in contrast to well-structured signaling domains of SRs, those of MIRRs represent intrinsically disordered regions, the regions that lack a well-defined three-dimensional structure under physiological conditions. Why did nature separate recognition and signaling functions of MIRRs? Why for MIRRs did nature select to provide highly specific signaling through the chaos of protein disorder? What mechanisms could control this chaos in the process of transmembrane signal transduction to provide the specificity and diversity of the immune response? Here, I summarize recent findings that may not only shed light on these and other questions but also add significantly to our understanding of receptor signaling, a fundamental process that plays a critical role in health and disease.




REVIEWS

Open Access Article

Adoptive immunotherapy of cancer: Gene transfer of T cell specificity

Amir A. Al-Khami, Shikhar Mehrotra and Michael I. Nishimura
Pages 80 - 84
http://dx.doi.org/10.4161/self.2.2.15832
Abstract | PDF

Adoptive transfer of tumor-reactive T cells has emerged as a promising advance in tumor immunotherapy. Specifically, infusion of tumor-infiltrating lymphocytes has led to long-term objective clinical responses for patients with metastatic melanoma. Donor lymphocyte infusion is also an effective treatment of post-transplant lymphoproliferative disease. However, adoptive T cell therapy has restrictions in the isolation and expansion of antigen-specific lymphocytes for a large group of patients. One approach to circumvent this limitation and extend adoptive immunotherapy to other cancer types is the genetic modification of T cells with antigen-specific receptors. In this article, we review strategies to redirect T cell specificity, including T cell receptor gene transfer and antibody receptor gene transfer. 

Open Access Article

Visualization of cell‑cell interaction contacts: Synapses and kinapses

Michael L. Dustin
Pages 85 - 97
http://dx.doi.org/10.4161/self.2.2.17931
Abstract | PDF

T‑cell activation requires interactions of T‑cell antigen receptors (TCR) and peptides presented by major histocompatibility complex molecules (MHCp) in an adhesive junction between the T‑cell and antigen‑presenting cell (APC). Stable junctions with bull’s eye supramolecular activation clusters (SMACs) have been defined as immunological synapses. The term synapse works in this case because it joins roots for “same” and “fasten,” which could be translated as “fasten in the same place.” These structures maintain T‑cell‑APC interaction and allow directed secretion. We have proposed that SMACs are not really clusters, but are analogous to higher order membrane‑cytoskeleton zones involved in amoeboid locomotion including a substrate testing lamellipodium, an adhesive lamella and anti‑adhesive uropod. Since T‑cells can also integrate signaling during locomotion over antigen presenting cells, it is important to consider adhesive junctions maintained as cells move past each other. This combination of movement (kine‑) and fastening (‑apse) can be described as a kinapse or moving junction. Synapses and kinapses operate in different stages of T‑cell priming. Optimal effector functions may also depend upon cyclical use of synapses and kinapses. Visualization of these structures in vitro and in vivo presents many distinct challenges that will be discussed in this chapter.

Open Access Article

Visualization of protein interactions in living cells

Tomasz Zal
Pages 98 - 107
http://dx.doi.org/10.4161/self.2.2.17932
Abstract | PDF

Ligand binding to cell membrane receptors sets off a series of protein interactions that convey the nuances of ligand identity to the cell interior. The information may be encoded in conformational changes, the interaction kinetics and, in the case of multichain immunoreceptors, by chain rearrangements. The signals may be modulated by dynamic compartmentalization of the cell membrane, cellular architecture, motility, and activation—all of which are difficult to reconstitute for studies of receptor signaling in vitro. In this chapter, we will discuss how protein interactions in general and receptor signaling in particular can be studied in living cells by different fluorescence imaging techniques. Particularly versatile are methods that exploit Förster resonance energy transfer (FRET), which is exquisitely sensitive to the nanometer‑range proximity and orientation between fluorophores. Fluorescence correlation microscopy (FCM) can provide complementary information about the stoichiometry and diffusion kinetics of large complexes, while bimolecular fluorescence complementation (BiFC) and other complementation techniques can capture transient interactions. A continuing challenge is extracting from the imaging data the quantitative information that is necessary to verify different models of signal transduction.




REPORTS

Open Access Article

HCV: Written in our DNA

Darja Kanduc
Pages 108 - 113
http://dx.doi.org/10.4161/self.2.2.15795
Abstract | PDF

An inspection of the sequence similarity between the hepatitis C virus (HCV) polyprotein and human proteins revealed a high level of peptide sharing, with a limited number of motifs unique to the virus (i.e., with no counterpart in the human proteome). Using pentapeptide matching, only 214 motifs out of a total of 3,007 (7.11%) identified HCV as nonself compared to the Homo sapiens proteome. However, this virus-versus-human phenetic difference disappeared at the genetic level. Indeed, a BLAST analysis of pentadecameric oligodeoxynucleotide sequences corresponding to the 214 pentapeptides unique to HCV revealed that almost all of them are present in the human genome, located in the non-coding strand, introns, and/or pseudogenes, thus being, as such, untranslatable. The present data warn against using DNA-based vaccines to fight HCV infection and emphasize peptide uniqueness as the molecular basis for designing effective anti-HCV immunotherapeutic approaches. 

Open Access Article

Selfness-nonselfness in designing an anti-B19 erythrovirus vaccine

Candida Fasano and Darja Kanduc
Pages 114 - 119
http://dx.doi.org/10.4161/self.2.2.16190
Abstract | PDF

Although B19 erythrovirus infection may be associated with severe clinical outcomes, especially in early infancy, pregnancy, and in immunocompromised or hemolytic subjects, no vaccine is currently available. Using the concept that effective immune responses to an infectious agent may be restricted to the specific peptidome unique to that agent, we analyzed primary amino acid sequence of B19 erythrovirus, searching for peptide motifs to be used in vaccine formulations. Here, we identify and describe a set of unique viral peptides that may guarantee both high efficacy and practically no cross-reactive autoimmune responses in anti-B19 immunotherapeutic approaches.

Open Access Article

Cytokine gene expression in the skin and peripheral blood of atopic dermatitis patients and healthy individuals

Elena S. Fedenko, Olga G. Elisyutina, Tatiana M. Filimonova, Margarita N. Boldyreva, O. V. Burmenskaya, O. Yu Rebrova, A. A. Yarilin and Rakhim M. Khaitov
Pages 120 - 124
http://dx.doi.org/10.4161/self.2.2.16939
Abstract | PDF

OBJECTIVES: Atopic dermatitis (AD) is an increasingly common, chronic, relapsing, inflammatory skin disease characterized by impaired epidermal barrier function and cutaneous inflammation. The prevalence of AD has steadily increased during the past few decades. The aim of this study was to comparatively investigate cytokine gene expression in the skin and peripheral blood of atopic dermatitis patients and healthy individuals. METHODS: Samples of skin and peripheral blood from 48 severe AD patients (SCORAD = 78,5 [57;89], IGA=4,2 [3,9;4,7]) at the age of 17 to 45 years and 20 healthy donors aged from 19 to 32 years were analyzed for gene expression of cytokines using real-time reverse transcription polymerase chain reaction (RT-PCR). RESULTS: In the skin of patients with AD, a significant increase of the level of gene expression was observed for interleukin (IL)-2r (p<0,0023), IL-5 (p=0,002), IL-6 (p<0,0023), IL-8 (p=0,01), IL-12B (p<0,0023), IL-10 (p<0,0023), IL-23 (p=0,002), IL-29 (p<0,0023), and transforming growth factor beta (TGF-beta) (p<0,0023) as compared to healthy individuals. In contrast, no difference between AD patients and healthy donors was detected with respect to cytokine gene expression in the peripheral blood. CONCLUSIONS: Activity of IL-2r, IL-5, IL-8, IL-12B, IL-23, IL-29, and TGF-beta that are markers of chronic inflammation and Th1 immune response in severe AD was predominant in the skin but not in the blood of AD patients.