June 2015 | Volume 212, No. 7
- Therapeutic targeting of autophagy in neurodegenerative and infectious diseases
Rubinsztein, Bento, and Deretic discuss the beneficial roles of autophagy in the context of infectious and neurodegenerative diseases.
Brief Definitive Reports
- A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules
Aspelund et al. discover the presence of a lymphatic vessel network in the dura mater of the mouse brain and show that these dural lymphatic vessels are important for the clearance of macromolecules from the brain.
- c-Myb is required for plasma cell migration to bone marrow after immunization or infection
The transcription factor c-Myb plays a role in establishing long-lived plasma cell populations in the bone marrow by affecting migration responses to chemokine gradients. The absence of c-Myb results in an absence of IgG+ antigen-specific plasma cells in the bone marrow following immunization or virus infection.
- The lysophosphatidylserine receptor GPR174 constrains regulatory T cell development and function
Barnes et al. show that a bioactive lipid, lysophosphatidylserine, negatively influences T reg cell accumulation and activity through one of its receptors, GPR174. The authors speculate that GPR174 antagonism may be therapeutic for autoimmune diseases.
- Endothelial CD99 signals through soluble adenylyl cyclase and PKA to regulate leukocyte transendothelial migration
CD99 is a critical regulator of leukocyte transendothelial migration (TEM). Watson et al. describe the CD99 signaling pathway responsible. This involves a complex of CD99 with the A-kinase anchoring protein ezrin and soluble adenylyl cyclase that activates protein kinase A during leukocyte TEM.
- CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages
Kitamura et al. find a role for metastasis-associated macrophage (MAM) chemokine pathways CCL2–CCR2 and CCL3–CCR1 in promoting breast cancer cell pulmonary metastasis. Genetic deletion of CCR1 or CCL3 in a mouse model of breast cancer cell metastasis prevents MAM retention in the lung, reduces MAM-cancer cell interactions and reduces the number of lung metastatic foci.
- The Dishevelled-binding protein CXXC5 negatively regulates cutaneous wound healing
In human melanoma biopsies and a murine cutaneous wound model, Lee et al. identify the Dishevelled-binding protein CXXC5 as a negative modulator of skin wound healing. CXXC5-deficient mice present accelerated wound healing as well as keratin and collagen synthesis. CXXC5, interacting with Dvl, operates as a negative feedback regulator of Wnt/β-catenin signaling and may represent a potential target for wound treatment.
- Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-α receptor signaling
Holmes et al. demonstrate that the protein tyrosine phosphatase PEP (PTPN22 in humans) associated with lupus and other autoimmune diseases, inhibits IFN-α receptor signaling in mice. PEP-deficient hematopoietic progenitors demonstrate increased IFNAR signaling, IFN-inducible gene expression and proliferation. PEP-deficient mice treated with IFN-α exhibit lupus-like disease and profound defects in hematopoiesis, resulting in cytopenia.
- Identification of phenotypically and functionally heterogeneous mouse mucosal-associated invariant T cells using MR1 tetramers
Rahimpour et al. use MR1 tetramers to characterize the heterogeneous population of mouse MAIT cells and find a close resemblance to their human counterparts. These findings will provide the foundation for further investigation of MAIT cells in health and disease.
- Combined heterozygous loss of Ebf1 and Pax5 allows for T-lineage conversion of B cell progenitors
Ungerbäck et al. show that transcription factors Ebf1 and Pax5 act in a coordinated, dose-dependent manner to preserve B-lineage cell fate. Combined heterozygous loss of both transcription factors results in increased T cell lineage skewing in B cell progenitors.
- Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells
Using PD-1–deficient mice and co-adoptive transfer approaches, Odorizzi et al. demonstrate that PD-1 is not required for the induction of CD8+ T cell exhaustion (TEX) in chronic LCMV infection. The absence of PD-1 leads to more cytotoxic, but terminally differentiated TEX, with compromised long-term durability. PD-1 may well serve to protect TEX from excessive overstimulation, proliferation, and terminal differentiation.