Volume 19 Issue 12, December 2018

The mechanism of action of the lymphocyte checkpoint protein LAG-3 was always rather mysterious. It now seems to operate at least in part by recognizing and suppressing responses to stable complexes of peptide and major histocompatibility complex class II.

A new model proposes that an applied force allows the co-receptor CD8 and the kinase Lck to selectively stabilize TCR interactions with negatively selecting ligands, but not those with positively selecting ligands, during the negative selection of self-reactive thymocytes.

Acidic microenvironments induced by highly glycolytic tumor cells promote the noninflammatory polarization of tumor-associated macrophages, which leads to immunoevasion.

Transcription factors orchestrate stage-specific gene expression during development. Two such factors, TCF-1 and HEB, collaborate at the protein and genomic levels to regulate gene expression in developing thymocytes.

Kabashima and colleagues review inflammatory skin disorders by discussing the pathogenesis of atopic dermatitis and psoriasis.

Pneumococcal carriage in the upper respiratory tract is an important determinant of influenza severity. Jochems et al. use human systems analysis to show that influenza-induced inflammation increases bacterial burden in the nasal cavity with implications for secondary bacterial pneumonia.

Endosomal TLR4 signaling activates type I interferons via a TRIF-dependent pathway. Vogel and colleagues identify autocrine production of PGE₂–EP4–cAMP as a negative regulator of the TRIF pathway that suppresses IFN-β expression induced by Gram-negative bacteria.

Tumors can vary in both their control by immunosurveillance and their glycolytic activity. Bopp and colleagues demonstrate that highly glycolytic tumors acidify their microenvironment and use this to initiate a mechanism of localized immunosuppression.

Obesity is a risk factor for cancer. Lynch and colleagues show that obesity alters the cellular metabolism of natural killer cells and decreases their antitumor surveillance and effector responses.

Korn and colleagues show that PMN-MDSCs restrain B cell accumulation in the central nervous system in autoimmune inflammation.

Hayday and colleagues show that the responsiveness of mouse and human γδ IELs to Btnl or BTNL proteins is mediated by germline-encoded motifs within the cognate TCR V_γ chains, while V_γ chain motifs generated by somatic gene rearrangement remain available for nominal antigen binding.

Thymocyte development requires a complex orchestration of multiple transcription factors. Gournari and colleagues find that Tcf-1 and HEB cooperate to establish the epigenetic and transcription profiles of CD4⁺CD8⁺ thymocytes

Zhu and colleagues show that negative-selection ligands induce cooperative TCR–pMHC–CD8 trimolecular ‘catch bonds’, whereas positive-selection ligands induce TCR–pMHC and pMHC–CD8 bimolecular ‘slip bonds’.

Regulatory T cells (T_reg cells) can destabilize in inflammatory environments. Sumida et al. show that β-catenin signaling perturbs T_reg cell function in patients with multiple sclerosis and under experimental high-salt conditions.

T_reg cells are essential for enforcing peripheral tolerance but can also influence tissue regeneration. Afzali and colleagues use high-dimensional analysis to describe a distinct population of CD161⁺ human T_reg cells involved in wound healing of the intestinal mucosa.

LAG-3 is a co-inhibitory receptor on T cells, but its mode of action is controversial. Okazaki and colleagues demonstrate that LAG-3 preferentially binds stable MHC class II complexes and thereby selectively maintains tolerance of self-reactive T cells.

Bcl11b is needed to establish T cell–lineage identity. Rothenberg and colleagues provide a comprehensive analysis of Bcl11b–cofactor interactions and reveal the functional relevance of direct and indirect Bcl11b binding activity in thymocytes.