Spike timing-dependent plasticity (STDP) as a Hebbian synaptic learning rule has been demonstrated in various neural circuits over a wide spectrum of species, from insects to humans. The dependence of synaptic modification on the order of pre- and postsynaptic spiking within a critical window of tens of milliseconds has profound functional implications. Over the past decade, significant progress has been made in understanding the cellular mechanisms of STDP at both excitatory and inhibitory synapses and of the associated changes in neuronal excitability and synaptic integration. Beyond the basic asymmetric window, recent studies have also revealed several layers of complexity in STDP, including its dependence on dendritic location, the nonlinear integration of synaptic modification induced by complex spike trains, and the modulation of STDP by inhibitory and neuromodulatory inputs. Finally, the functional consequences of STDP have been examined directly in an increasing number of neural circuits in vivo.

Spike timing-dependent plasticity: a Hebbian learning rule

Almost all of the key molecules involved in the innate and adaptive immune response are glycoproteins. In the cellular immune system, specific glycoforms are involved in the folding, quality control, and assembly of peptide-loaded major histocompatibility complex (MHC) antigens and the T cell receptor complex. Although some glycopeptide antigens are presented by the MHC, the generation of peptide antigens from glycoproteins may require enzymatic removal of sugars before the protein can be cleaved. Oligosaccharides attached to glycoproteins in the junction between T cells and antigen-presenting cells help to orient binding faces, provide protease protection, and restrict nonspecific lateral protein-protein interactions. In the humoral immune system, all of the immunoglobulins and most of the complement components are glycosylated. Although a major function for sugars is to contribute to the stability of the proteins to which they are attached, specific glycoforms are involved in recognition events. For example, in rheumatoid arthritis, an autoimmune disease, agalactosylated glycoforms of aggregated immunoglobulin G may induce association with the mannose-binding lectin and contribute to the pathology.

http://science.sciencemag.org/content/sci/291/5512/2370.full.pdf

Glycosylation and the immune system

■ Abstract Correlated spiking of pre- and postsynaptic neurons can result in strengthening or weakening of synapses, depending on the temporal order of spiking. Recent findings indicate that there are narrow and cell type‐specific temporal windows for such synaptic modification and that the generally accepted input- (or synapse-) specific rule for modification appears not to be strictly adhered to. Spike timing‐ dependent modifications, together with selective spread of synaptic changes, provide a set of cellular mechanisms that are likely to be important for the development and functioning of neural networks. When an axon of cell A is near enough to excite cell B or repeatedly or consistently takes part in firing it, some growth or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased. Donald Hebb (1949)

/pdf/synaptic-modification-by-correlated-activity-hebb-s-1q5x2b0tjh.pdf

Synaptic Modification by Correlated Activity: Hebb's Postulate Revisited

Since the first crystal structure determinations of alphabeta T cell receptors (TCRs) bound to class I MHC-peptide (pMHC) antigens in 1996, a sizable database of 24 class I and class II TCR/pMHC complexes has been accumulated that now defines a substantial degree of structural variability in TCR/pMHC recognition. Recent determination of free and bound gammadelta TCR structures has enabled comparisons of the modes of antigen recognition by alphabeta and gammadelta T cells and antibodies. Crystal structures of TCR accessory (CD4, CD8) and coreceptor molecules (CD3epsilondelta, CD3epsilongamma) have further advanced our structural understanding of most of the components that constitute the TCR signaling complex. Despite all these efforts, the structural basis for MHC restriction and signaling remains elusive as no structural features that define a common binding mode or signaling mechanism have yet been gleaned from the current set of TCR/pMHC complexes. Notwithstanding, the impressive array of self, foreign (microbial), and autoimmune TCR complexes have uncovered the diverse ways in which antigens can be specifically recognized by TCRs.

How TCRs Bind MHCs, Peptides, and Coreceptors

▪ Abstract While still incomplete, the first data concerning the biochemistry of T cell receptor–ligand interactions in cell-free systems seem to have considerable predictive value regarding whether a T cell response is strong or weak or suppressive. This data will help considerably in elucidating the mechanisms behind T cell responsiveness. Also of great interest are the first structures of T cell receptor molecules and, particularly, TCR-ligand complexes. These appear to confirm earlier suggestions of a fixed orientation for TCR engagement with peptide/MHC and should form the basis for understanding higher oligomers, evidence for which has also just emerged. We conclude with an analysis of the highly diverse CDR3 loops found in all antigen receptor molecules and suggest that such regions form the core of both TCR and antibody specificity.

Ligand recognition by alpha beta T cell receptors.

The dimeric cell-surface glycoprotein CD8 is crucial to the positive selection of cytotoxic T cells in the thymus. The homodimer CD8alpha(alpha) or the heterodimer alpha beta stabilizes the interaction of the T-cell antigen receptor (TCR) with major histocompatibility complex (MHC) class I/peptide by binding to the class I molecule. Here we report the crystal structure at 2.7 A resolution of a complex between CD8alpha(alpha) and the human MHC molecule HLA-A2, which is associated with peptide. CD8alpha(alpha) binds one HLA-A2/peptide molecule, interfacing with the alpha2 and alpha3 domains of HLA-A2 and also contacting beta2-microglobulin. A flexible loop of the alpha3 domain (residues 223-229) is clamped between the complementarity-determining region (CDR)-like loops of the two CD8 subunits in the classic manner of an antibody-antigen interaction, precluding the binding of a second MHC molecule. The position of the alpha3 domain is different from that in uncomplexed HLA-A2, being most similar to that in the TCR/Tax/HLA-A2 complex, but no conformational change extends to the MHC/peptide surface presented for TCR recognition. Although these shifts in alpha3 may provide a synergistic modulation of affinity, the binding of CD8 to MHC is clearly consistent with an avidity-based contribution from CD8 to TCR-peptide-MHC interactions.

Crystal structure of the complex between human CD8αα and HLA-A2

. The absolute hand of the map was determined by ensuring that the angle of tilted views of the two-dimensional crystal was recorded with the correct sign. As a check for the assignment of the sign of the tilt angles, we used two-dimensional crystals of bacteriorhodopsin (purple membrane) for which the hand is known. Images recorded from tilted, glucoseembedded purple membrane samples were subjected to the same protocol as our analysis of AQP1, and the resulting phases were compared with the reported phases for purple membrane 26 . Search for non-crystallographic symmetry was performed by calculating the rotation function using the program POLARRFN in the CCP4 package 27 . A non-crystallographic peak in the membrane plane was consistently seen for all resolution ranges (data not shown). This peak corresponds to a 2-fold rotation axis inclined by 88 with respect to the unit cell a (or b) axis and has the maximum strength for a radius of integration of 40 A ˚ .

http://www.caspmi.cn/gaog/pdf/1.%a1%b6Nature%a1%b7-1997-George%20Fu%20Gao.pdf

Crystal structure of the complex between human CD8aa and HLA-A2

T cell receptor and coreceptor CD8 alphaalpha bind peptide-MHC independently and with distinct kinetics.

The CD8 co-receptor is important in the differentiation and selection of class I MHC-restricted T cells during thymic development, and in the activation of mature T lymphocytes in response to antigen. Here we show that soluble CD8alphaalpha receptor, despite an extremely low affinity for MHC, inhibits activation of cytotoxic lymphocytes by obstructing CD3 zeta-chain phosphorylation. We propose a model for this effect that involves interference of productive receptor multimerization at the T-cell surface. These results provide new insights into the mechanism of T-cell activation and evidence that CD8 function is exquisitely sensitive to disruption, an effect that might be exploited by molecular therapeutics.

Antagonism of cytotoxic T-lymphocyte activation by soluble CD8.

A strategy for overexpression in Escherichia coli of the extracellular immunoglobulin domain of human CD8alpha was devised using codon usage alterations in the 5' region of the gene, designed so as to prevent the formation of secondary structures in the mRNA. A fragment of CD8alpha, comprising residues 1-120 of the mature protein, excluding the signal peptide and the membrane-proximal stalk region, was recovered from bacterial inclusion bodies and refolded to produce a single species of homodimeric, soluble receptor. HLA-A2 heavy chain, beta2-microglobulin and a synthetic peptide antigen corresponding to the pol epitope from HIV-1 were also expressed in E. coli, refolded and purified. CD8alpha/HLA-A2 complexes were formed in solution and by co-crystallization with a stoichiometry of one CD8alpha alpha dimer to one HLA-A2-peptide unit.

/pdf/assembly-and-crystallization-of-the-complex-between-the-3bz1qe10ch.pdf

U. C. Gerth

Papers

Crystal structure of the complex between human CD8αα and HLA-A2

Crystal structure of the complex between human CD8aa and HLA-A2

T cell receptor and coreceptor CD8 alphaalpha bind peptide-MHC independently and with distinct kinetics.

Antagonism of cytotoxic T-lymphocyte activation by soluble CD8.

Assembly and crystallization of the complex between the human t cell coreceptor cd8alpha homodimer and hla-a2