Efficacy and Safety of Durvalumab Combined with Daratumumab in Daratumumab-Refractory Multiple Myeloma Patients.

Daratumumab is active both as a single agent and in combination with other agents in multiple myeloma (MM) patients. However, the majority of patients will develop daratumumab-refractory disease, which carries a poor prognosis. Since daratumumab also has immunomodulatory effects, addition of the PD-L1 blocking antibody durvalumab at the time of progression may reverse daratumumab-resistance.

Longitudinal characterization of functional, morphologic, and biochemical adaptations in mouse skeletal muscle with hindlimb suspension.

Introduction: Hindlimb unloading-induced muscle atrophy is often assessed after a homeostatic state is established, thus overlooking the early adaptations that are critical to developing this pattern of atrophy.

Methods: Muscle function and physiology were characterized at 0, 1, 3, 7, and 14 days of hindlimb suspension (HS).

Results: Reductions in muscle mass were maximal by Day 14 of HS.

The Ikaros transcription factor regulates responsiveness to IL-12 and expression of IL-2 receptor alpha in mature, activated CD8 T cells.

The Ikaros family of transcription factors is critical for normal T cell development while limiting malignant transformation. Mature CD8 T cells express multiple Ikaros family members, yet little is known about their function in this context. To test the functions of this gene family, we used retroviral transduction to express a naturally occurring, dominant negative (DN) isoform of Ikaros in activated CD8 T cells.

MAIT cell recognition of MR1 on bacterially infected and uninfected cells.

Mucosal-associated invariant T cells are a unique population of T cells that express a semi-invariant αβ TCR and are restricted by the MHC class I-related molecule MR1. MAIT cells recognize uncharacterized ligand(s) presented by MR1 through the cognate interaction between their TCR and MR1. To understand how the MAIT TCR recognizes MR1 at the surface of APCs cultured both with and without bacteria, we undertook extensive mutational analysis of both the MAIT TCR and MR1 molecule.

Mucosal associated invariant T cells: don't forget your vitamins.

T lymphocytes express clonal receptors, called T cell receptors (TCRs), which specifically recognize antigens presented in combination with major histocompatibility molecules (MHC). To date, T cell antigens can be broadly categorized into two classes: peptides and lipids. A recent paper published in Nature by Kjer-Nielsen and colleagues reveals that a unique population of T lymphocytes expresses TCRs that recognize a completely new and unexpected class of antigens, vitamin metabolites.

In vivo measurement of hindlimb neuromuscular function in mice.

Introduction: In vitro or in situ methods to assess neuromuscular performance in rodents are invasive and inadequate to fully assess large hindlimb muscles.

Methods: An in vivo hindlimb exertion force test (HEFT) was developed to quantify muscle function peak force (PF), peak rate of force development (PRFD), and short- and long-latency reaction times (SLRT and LLRT, respectively) in C57BL/6J mice.

Results: PF did not change with one- and three-times-per-week repeated HEFT trials, demonstrating assessment reproducibility.

Evolutionarily conserved features contribute to αβ T cell receptor specificity.

αβ T cell receptors (TCRs) bind specifically to foreign antigens presented by major histocompatibility complex proteins (MHC) or MHC-like molecules. Accumulating evidence indicates that the germline-encoded TCR segments have features that promote binding to MHC and MHC-like molecules, suggesting coevolution between TCR and MHC molecules. Here, we assess directly the evolutionary conservation of αβ TCR specificity for MHC.

A molecular basis for NKT cell recognition of CD1d-self-antigen.

The antigen receptor for natural killer T cells (NKT TCR) binds CD1d-restricted microbial and self-lipid antigens, although the molecular basis of self-CD1d recognition is unclear. Here, we have characterized NKT TCR recognition of CD1d molecules loaded with natural self-antigens (Ags) and report the 2.3 Å resolution structure of an autoreactive NKT TCR-phosphatidylinositol-CD1d complex.

A molecular basis for the exquisite CD1d-restricted antigen specificity and functional responses of natural killer T cells.

Natural killer T (NKT) cells respond to a variety of CD1d-restricted antigens (Ags), although the basis for Ag discrimination by the NKT cell receptor (TCR) is unclear. Here we have described NKT TCR fine specificity against several closely related Ags, termed altered glycolipid ligands (AGLs), which differentially stimulate NKT cells. The structures of five ternary complexes all revealed similar docking.

Group 1 CD1-restricted T cells take center stage.

The recognition of lipid antigens by T cells is a complex and fascinating phenomenon. The MHC-like molecules of the CD1 family have evolved to present a wide variety of both self and foreign lipids for recognition by T-cell receptors. While much progress has been made in our understanding of the NKT cells that recognize lipids presented by CD1d molecules, our knowledge of the T-cell populations directed at the related group 1 CD1 molecules, i.

T cell receptor CDR2 beta and CDR3 beta loops collaborate functionally to shape the iNKT cell repertoire.

Mouse type I natural killer T cell receptors (iNKT TCRs) use a single V alpha 14-J alpha 18 sequence and V beta s that are almost always V beta 8.2, V beta 7, or V beta 2, although the basis of this differential usage is unclear. We showed that the V beta bias occurred as a consequence of the CDR2 beta loops determining the affinity of the iNKT TCR for CD1d-glycolipids, thus controlling positive selection.