N-terminal ectodomain of BTNL2 inhibits T cell activation via a non-canonical interaction with its putative receptor that results in a delayed progression of DSS-induced ulcerative colitis.

Butyrophilin-like 2 (BTNL2) is a T cell inhibitory molecule that interacts with unknown binding partners to modulate the immune response in a number of inflammatory and autoimmune diseases. In this study, we found that the inhibitory effects of BTNL2 on T cell activation and effector functions can be executed by its N-terminal IgV domain (BTNL2 IgV1) alone. Structure-guided mutation of key residues on BTNL2 IgV1 based on known receptor-ligand interfaces involving immunoglobulin superfamily members revealed that BTNL2 uses a non-canonical binding interface with its putative receptor. A high avidity BTNL2 IgV1 probe revealed that in an inducible model of ulcerative colitis, severe colitis was accompanied by a selective enrichment of BTNL2-receptor expressing effector-memory CD4+ and CD8+ T cells in the Peyer's patches. Intraperitoneal administration of BTNL2 IgV1 resulted in a significant delay in the progression of DSS-induced colitis and also showed reduced activation of the BTNL2-receptor-expressing T cells in the Peyer's patches. Thus, this study demonstrates that the BTNL2-receptor-expressing T cells in the Peyer's patches participate in the disease pathogenesis and can serve as a novel therapeutic target in ulcerative colitis, which can be modulated by BTNL2 IgV1.

Transition metallo-curcumin complexes: a new hope for endometriosis?

Endometriosis is a debilitating gynecological disorder in women of reproductive age. Laparoscopy, a minimally invasive surgical procedure, provides a definitive diagnosis of the disease. Current treatments, including hormonal therapy and pain medication, are often associated with undesirable side effects limiting their long-term usage. This calls for exploring newer diagnostic and therapeutic options with minimal side effects. Curcumin is an established anti-endometriotic agent with inherent fluorescent properties; however, poor bioavailability limits its clinical utility. To address this shortcoming, various transition metals were conjugated with curcumin to improve its stability, specificity and pharmacological properties. The chemical stability, hemocompatibility and ability of the synthesized metallo-curcumin complexes (MCCs) to ameliorate endometriotic lesions were investigated. While all of the MCCs exhibited low hemolytic activity, their chemical and biological activities were largely dependent on the nature of the metal ion conjugated to the curcumin molecule. Copper-curcumin and nickel-curcumin complexes demonstrated superior therapeutic efficacy evidenced by enhanced antioxidant activity, selective cytotoxicity and increased accumulation in endometriotic cells mediated by an energy-dependent active transport process.

Heterophilic recognition between E-cadherin and N-cadherin relies on same canonical binding interface as required for E-cadherin homodimerization.

Cadherins are a family of cell surface glycoproteins that mediate Ca2+-dependent cell to cell adhesion. They organize to form large macromolecular assemblies at the junctions of cells in order to form and maintain the integrity of tissue structures, thereby playing an indispensable role in the multicellular organization. Notably, a large body of research on E- and N-cadherin, the two most widely studied members of the cadherin superfamily, suggest for homophilic associations among them to drive cell adhesion. Interestingly, latest studies also highlight for direct crosstalk among these two classical cadherins to form heterotypic connections in physiological as well as in disease environment. However, the molecular details for the heterophilic association of E-cadherin and N-cadherin has not been investigated yet, which we aimed to address in this work. Using surface plasmon resonance and flow cytometry based biophysical studies we observed heterophilic interaction between E- and N-cadherin mediated through the membrane distal ectodomains. Further, the heterodimeric interface of E-cadherin and N-cadherin was mapped using structure-guided mutational studies followed by complementary biophysical analyses to identify the important interface residues involved in the interaction. The results obtained imply significant resemblance in the interface residues of E-cadherin that are crucial for homophilic recognition of E-cadherin and heterophilic recognition of N-cadherin as well.

Plasma therapy: a passive resistance against the deadliest.

Convalescent plasma therapy provides a useful therapeutic tool to treat infectious diseases, especially where no specific therapeutic strategies have been identified. The ongoing pandemic puts back the spotlight on this age-old method as a viable treatment option. In this review, we discuss the usage of this therapy in different diseases including COVID-19, and the possible mechanisms of action. The current review also discusses the progress of therapeutic applications of blood-derivatives, from the simple transfer of immunized animal sera, to the more target-specific intravenous administration of human immunoglobulins from a pool of convalescent individuals, in both infectious and non-infectious diseases of various etiologies.

Structural Insights into N-terminal IgV Domain of BTNL2, a T Cell Inhibitory Molecule, Suggests a Non-canonical Binding Interface for Its Putative Receptors.

T cell costimulation is mediated by the interaction of a number of receptors and ligands present on the surface of the T cell and antigen-presenting cell, respectively. Stimulatory or inhibitory signals from these receptor-ligand interactions work in tandem to preserve immune homeostasis. BTNL2 is a type-1 membrane protein that provides inhibitory signal to T cells and plays an important role in several inflammatory and autoimmune diseases. Therefore, manipulation of the molecular interaction of BTNL2 with its putative receptor could provide strategies to restore immune homeostasis in these diseases. Hence, it is imperative to study the structural characteristics of this molecule, which will provide important insights into its function as well. In this study, the membrane-distal ectodomain of murine BTNL2 was expressed in bacteria as inclusion bodies, refolded in vitro and purified for functional and structural characterization. The domain is monomeric in solution as demonstrated by size-exclusion chromatography and analytical ultracentrifugation, and also binds to its putative receptor on naïve B cells and activated T cell subsets. Importantly, for the first time, we report the structure of BTNL2 as determined by solution NMR spectroscopy and also the picosecond-nanosecond timescale backbone dynamics of this domain. The N-terminal ectodomain of BTNL2, which was able to inhibit T cell function as well, exhibits distinctive structural features. The N-terminal ectodomain of BTNL2 has a significantly reduced surface area in the front sheet due to the non-canonical conformation of the CC' loop, which provides important insights into the recognition of its presently unknown binding partner.