Peripheral Tissue Chemokines: Homeostatic Control of Immune Surveillance T Cells.

Cellular immunity is governed by a complex network of migratory cues that enable appropriate immune cell responses in a timely and spatially controlled fashion. This review focuses on the chemokines and their receptors regulating the steady-state localisation of immune cells within healthy peripheral tissues. Steady-state immune cell traffic is not well understood but is thought to involve constitutive (homeostatic) chemokines. The recent discovery of tissue-resident memory T cells (TRM cells) illustrates our need for understanding how chemokines control immune cell mobilisation and/or retention. These studies will be critical to unravel novel pathways for preserving tissue function (aging) and preventing tissue disease (vaccination).

γδ T cell responses: How many ligands will it take till we know?

γδ T cells constitute a sizeable and non-redundant fraction of the total T cell pool in all jawed vertebrates, but in contrast to conventional αß T cells they are not restricted by classical MHC molecules. Progress in our understanding of the role of γδ T cells in the immune system has been hampered, and is being hampered, by the considerable lack of knowledge regarding the antigens γδ T cells respond to. The past few years have seen a wealth of data regarding the TCR repertoires of distinct γδ T cell populations and a growing list of confirmed and proposed molecules that are recognised by γδ T cells in different species. Yet, the physiological contexts underlying the often restricted TCR usage and the chemical diversity of γδ T cell ligands remain largely unclear, and only few structural studies have confirmed direct ligand recognition by the TCR. We here review the latest progress in the identification and validation of putative γδ T cell ligands and discuss the implications of such findings for γδ T cell responses in health and disease.

CXCL14 Preferentially Synergizes With Homeostatic Chemokine Receptor Systems.

Reflecting their importance in immunity, the activity of chemokines is regulated on several levels, including tissue and context-specific expression and availability of their cognate receptor on target cells. Chemokine synergism, affecting both chemokine and chemokine receptor function, has emerged as an additional control mechanism. We previously demonstrated that CXCL14 is a positive allosteric modulator of CXCR4 in its ability to synergize with CXCL12 in diverse cellular responses. Here, we have extended our study to additional homeostatic, as well as a selection of inflammatory chemokine systems. We report that CXCL14 strongly synergizes with low (sub-active) concentrations of CXCL13 and CCL19/CCL21 in in vitro chemotaxis with immune cells expressing the corresponding receptors CXCR5 and CCR7, respectively. CXCL14 by itself was inactive, not only on cells expressing CXCR5 or CCR7 but also on cells expressing any other known conventional or atypical chemokine receptor, as assessed by chemotaxis and/or ß-arrestin recruitment assays. Furthermore, synergistic migration responses between CXCL14 and inflammatory chemokines CXCL10/CXCL11 and CCL5, targeting CXCR3 and CCR5, respectively, were marginal and occasional synergistic Ca2+ flux responses were observed. CXCL14 bound to 300-19 cells and interfered with CCL19 binding to CCR7-expressing cells, suggesting that these cellular interactions contributed to the reported CXCL14-mediated synergistic activities. We propose a model whereby tissue-expressed CXCL14 contributes to cell localization under steady-state conditions at sites with prominent expression of homeostatic chemokines.

A Novel Small-Molecule Inhibitor of MRCK Prevents Radiation-Driven Invasion in Glioblastoma.

Glioblastoma (GBM) is an aggressive and incurable primary brain tumor that causes severe neurologic, cognitive, and psychologic symptoms. Symptoms are caused and exacerbated by the infiltrative properties of GBM cells, which enable them to pervade the healthy brain and disrupt normal function. Recent research has indicated that although radiotherapy (RT) remains the most effective component of multimodality therapy for patients with GBM, it can provoke a more infiltrative phenotype in GBM cells that survive treatment. Here, we demonstrate an essential role of the actin-myosin regulatory kinase myotonic dystrophy kinase-related CDC42-binding kinase (MRCK) in mediating the proinvasive effects of radiation. MRCK-mediated invasion occurred via downstream signaling to effector molecules MYPT1 and MLC2. MRCK was activated by clinically relevant doses per fraction of radiation, and this activation was concomitant with an increase in GBM cell motility and invasion. Furthermore, ablation of MRCK activity either by RNAi or by inhibition with the novel small-molecule inhibitor BDP-9066 prevented radiation-driven increases in motility both in vitro and in a clinically relevant orthotopic xenograft model of GBM. Crucially, treatment with BDP-9066 in combination with RT significantly increased survival in this model and markedly reduced infiltration of the contralateral cerebral hemisphere.Significance: An effective new strategy for the treatment of glioblastoma uses a novel, anti-invasive chemotherapeutic to prevent infiltration of the normal brain by glioblastoma cells.Cancer Res; 78(22); 6509-22. ©2018 AACR.