Andrej Kosmrlj

Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection

Without therapy, most people infected with human immunodeficiency virus (HIV) ultimately progress to AIDS. Rare individuals (‘elite controllers’) maintain very low levels of HIV RNA without therapy, thereby making disease progression and transmission unlikely. Certain HLA class I alleles are markedly enriched in elite controllers, with the highest association observed for HLA-B57 (ref. 1). Because HLA molecules present viral peptides that activate CD8+ T cells, an immune-mediated mechanism is probably responsible for superior control of HIV. Here we describe how the peptide-binding characteristics of HLA-B57 molecules affect thymic development such that, compared to other HLA-restricted T cells, a larger fraction of the naive repertoire of B57-restricted clones recognizes a viral epitope, and these T cells are more cross-reactive to mutants of targeted epitopes. Our calculations predict that such a T-cell repertoire imposes strong immune pressure on immunodominant HIV epitopes and emergent mutants, thereby promoting efficient control of the virus. Supporting these predictions, in a large cohort of HLA-typed individuals, our experiments show that the relative ability of HLA-B alleles to control HIV correlates with their peptide-binding characteristics that affect thymic development. Our results provide a conceptual framework that unifies diverse empirical observations, and have implications for vaccination strategies.

How a protein searches for its site on DNA: the mechanism of facilitated diffusion

A number of vital biological processes rely on fast and precise recognition of a specific DNA sequence (site) by a protein. How can a protein find its site on a long DNA molecule among 10 6 ‐10 9 decoy sites? Here, we present our recent studies of the protein‐DNA search problem. Seminal biophysical works suggested that the protein‐DNA search is facilitated by 1D diffusion of the protein along DNA (sliding). We present a simple framework to calculate the mean search time and focus on several new aspects of the process such as the roles of DNA sequence and protein conformational flexibility. We demonstrate that coupling of DNA recognition with conformational transition within the protein‐DNA complex is essential for fast search. To approach the complexity of the in vivo environment, we examine how the search can proceed at realistic DNA concentrations and binding constants. We propose a new mechanism for local distance-dependent search that is likely essential in bacteria. Simulations of the search on tightly packed DNA and crowded DNA demonstrate that our theoretical framework can be extended to correctly predicts search time in such complicated environments. We relate our findings to a broad range of experiments and summarize the results of our recent singlemolecule studies of a eukaryotic protein (p53) sliding along DNA.

Soft spheres make more mesophases

We use both mean-field methods and numerical simulation to study the phase diagram of classical particles interacting with a hard-core and repulsive, soft shoulder. Despite the purely repulsive interaction, this system displays a remarkable array of aggregate phases arising from the competition between the hard-core and shoulder length scales. In the limit of large shoulder width to core size, we argue that this phase diagram has a number of universal features, and classify the set of repulsive shoulders that lead to aggregation at high density. Surprisingly, the phase sequence and aggregate size adjusts so as to keep almost constant inter-aggregate separation.

How the thymus designs antigen-specific and self-tolerant T cell receptor sequences

T lymphocytes (T cells) orchestrate adaptive immune responses that clear pathogens from infected hosts. T cells recognize short peptides (p) derived from antigenic proteins bound to protein products of the MHC genes. Recognition occurs when T cell receptor (TCR) proteins expressed on T cells bind sufficiently strongly to antigen-derived pMHC complexes on the surface of antigen-presenting cells. A diverse repertoire of self-pMHC-tolerant TCR sequences is shaped during development of T cells in the thymus by processes called positive and negative selection. Combining computational models and analysis of experimental data, we parsed the contributions of positive and negative selection to the design of TCR sequences that recognize antigenic peptides with specificity, yet also exhibit cross-reactivity. A dominant role for negative selection in mediating antigen specificity of mature T cells and a molecular mechanism for TCR recognition of antigen are described.

Harnessing instabilities for design of soft reconfigurable auxetic/chiral materials

Most materials have a unique form optimized for a specific property and function. However, the ability to reconfigure material structures depending on stimuli opens exciting opportunities. Although mechanical instabilities have been traditionally viewed as a failure mode, here we exploit them to design a class of 2D soft materials whose architecture can be dramatically changed in response to an external stimulus. By considering geometric constraints on the tessellations of the 2D Euclidean plane, we have identified four possible periodic distributions of uniform circular holes where mechanical instability can be exploited to reversibly switch between expanded (i.e. with circular holes) and compact (i.e. with elongated, almost closed elliptical holes) periodic configurations. Interestingly, in all these structures buckling is found to induce large negative values of incremental Poissons ratio and in two of them also the formation of chiral patterns. Using a combination of finite element simulations and experiments at the centimeter scale we demonstrate a proof-of-concept of the proposed materials. Since the proposed mechanism for reconfigurable materials is induced by elastic instability, it is reversible, repeatable and scale-independent.

Thymic Selection of T-Cell Receptors as an Extreme Value Problem

T lymphocytes (T cells) orchestrate adaptive immune responses upon activation. T-cell activation requires sufficiently strong binding of T-cell receptors on their surface to short peptides (p) derived from foreign proteins, which are bound to major histocompatibility gene products (displayed on antigen-presenting cells). A diverse and self-tolerant T-cell repertoire is selected in the thymus. We map thymic selection processes to an extreme value problem and provide an analytic expression for the amino acid compositions of selected T-cell receptors (which enable its recognition functions).

Statistical Mechanical Concepts in Immunology

Higher organisms, such as humans, have an adaptive immune system that usually enables them to successfully combat diverse (and evolving) microbial pathogens. The adaptive immune system is not preprogrammed to respond to prescribed pathogens. Yet it mounts pathogen-specific responses against diverse microbes and establishes memory of past infections (the basis of vaccination). Although major advances have been made in understanding pertinent molecular and cellular phenomena, the mechanistic principles that govern many aspects of an immune response are not known. We illustrate how complementary approaches from the physical and life sciences can help confront this challenge. Specifically, we describe work that brings together statistical mechanics and cell biology to shed light on how key molecular/cellular components of the adaptive immune system are selected to enable pathogen-specific responses. We hope these examples encourage physical chemists to work at this crossroad of disciplines where fundamental discoveries with implications for human health might be made.

Response of thermalized ribbons to pulling and bending

Motivated by recent free-standing graphene experiments, we show how thermal fluctuations affect the mechanical properties of microscopically thin solid ribbons, which can be many thousand times wider than their atomic thickness. A renormalization group analysis of flexural phonons reveals that elongated ribbons behave like highly anisotropic polymers, where the two dimensional nature of ribbons is reflected in nontrivial power law scalings of the persistence length and effective bending and twisting rigidities with the ribbon width. With a coarse-grained transfer matrix approach, we then examine the nonlinear response of thermalized ribbons to pulling and bending forces over a wide spectrum of temperatures, forces, and ribbon lengths.

Continuum Theory for Cluster Morphologies of Soft Colloids

We introduce a continuum description of the thermodynamics of colloids with a core-corona architecture. In the case of thick coronas, their overlap can be treated approximately by replacing the exact one-particle density distribution by a suitably shaped step profile, which provides a convenient way of modeling the spherical, columnar, lamellar, and inverted cluster morphologies predicted by numerical simulations and the more involved theories. We use the model to study monodisperse particles with the hard-core/square-shoulder pair interaction as the simplest representatives of the core-corona class. We derive approximate analytical expressions for the enthalpies of the cluster morphologies which offer a clear insight into the mechanisms at work, and we calculate the lattice spacing and the cluster size for all morphologies of the phase sequence as well as the phase-transition pressures. By comparing the results with the exact crystalline minimum-enthalpy configurations, we show that the accuracy of the theory increases with shoulder width. We discuss possible extensions of the theory that could account for the finite-temperature effects.

Spontaneous formation of aligned DNA nanowires by capillarity-induced skin folding

Significance Developing a method that is capable of manipulating the size, geometry, and alignment of DNA nanowires would expand their uses in fabricating functional materials and performing genetic analysis. Here, we present an approach that yields arrays of size-controllable straight or undulated DNA nanowires. This approach uses a template composed of a thin skin that dynamically changes its surface morphology in response to water. In particular, we exploit capillary forces of water containing DNA molecules to induce a wrinkle-to-fold transition of the template surface in an unconventional way, which in turn stretches and confines the molecules in the folded regions without any external forces and consequently forms the nanowires. This approach could make possible new fabrication opportunities for functional materials. Although DNA nanowires have proven useful as a template for fabricating functional nanomaterials and a platform for genetic analysis, their widespread use is still hindered because of limited control over the size, geometry, and alignment of the nanowires. Here, we document the capillarity-induced folding of an initially wrinkled surface and present an approach to the spontaneous formation of aligned DNA nanowires using a template whose surface morphology dynamically changes in response to liquid. In particular, we exploit the familiar wrinkling phenomenon that results from compression of a thin skin on a soft substrate. Once a droplet of liquid solution containing DNA molecules is placed on the wrinkled surface, the liquid from the droplet enters certain wrinkled channels. The capillary forces deform wrinkles containing liquid into sharp folds, whereas the neighboring empty wrinkles are stretched out. In this way, we obtain a periodic array of folded channels that contain liquid solution with DNA molecules. Such an approach serves as a template for the fabrication of arrays of straight or wrinkled DNA nanowires, where their characteristic scales are robustly tunable with the physical properties of liquid and the mechanical and geometrical properties of the elastic system.