Volume 22 Issue 6, June 2021

B cells rewire complement for optimal germinal center responses. When B cell C3 activity is limited, germinal centers collapse and outputs are impaired.

C-12, a cluster of CD4⁺ T_H17-like cells, defined by unbiased multimodal profiling of memory T cells, is significantly reduced in patients who have recovered from TB (progressors) as compared to those who were infected but did not develop the disease (non-progressors).

Single-cell RNA sequencing identifies an inflammatory subpopulation of mesenchymal stromal cells in patients with multiple myeloma.

Chromatin undergoes extensive reprogramming during immune cell differentiation. Histone clipping, an underexplored epigenetic mechanism, ensures precise macrophage development and function and is now found to be dysregulated in autoinflammatory disease.

Colonization of the mucosal tissues by iNKT cells was thought to be linked to the first contact with the environment. New research demonstrates that this process is regulated by and dependent on embryonic macrophages.

As a follow up to a 2010 meeting deliberating on the benefits of studying mouse models of systemic lupus erythematosus (SLE), the virtual conference “Mouse models of lupus 10 years later” convened on 10 December 2020 to address a challenging decade that saw few new therapies approved, despite leaps in knowledge.

In this Review, Mittelbrunn and Kroemer propose that ten molecular hallmarks represent the common denominators of T cell aging.

Invariant natural killer T (iNKT) cells populate barrier surfaces during an early-life window. Blumberg and colleagues demonstrate that such barrier surface iNKT cells develop via an extrathymic pathway dependent on a specialized population of embryo-derived macrophages.

Chromatin undergoes extensive reprogramming during immune cell differentiation. Here Kuo and colleagues uncover an epigenetic mechanism that primes the chromatin to facilitate macrophage development.

Dick and colleagues identify human LT-HSC subsets with distinct quiescent states. They link these differences to INKA1-mediated downregulation of the transmembrane protein CD112 and its interaction with the protein deacetylase SIRT1. INKA1 is inversely correlated with the histone H4K16Ac mark, which then distinguishes ‘latent’ CD112^lo LT-HSCs from CD112^hi LT-HSCs that are more readily activated in response to hematopoietic stress.

Human primary and metastatic tumors harbor CD4⁺ T_reg cells that can suppress antitumor immune responses. Bonnal et al. identify an intratumoral type 1 T_reg-like CD4⁺ T cell subset that expresses the transcription factor EOMES, granzyme K and CHI3L2. This EOMES⁺ T cell subset correlates with disease progression but is responsive to PD-1 checkpoint blockade immunotherapy.

Tang and colleagues show that a half-life-extended IL-10–Fc fusion protein acts directly on terminally exhausted PD1⁺TIM-3⁺CD8⁺ T cells to enhance their proliferation and effector function by reprogramming the cellular metabolism to oxidative phosphorylation in a mitochondrial pyruvate carrier–dependent manner. Treatment of tumor-bearing mice with IL-10–Fc and adoptive T cell therapy led to eradication of their established solid tumors and durable cures.

Heeger and colleagues report that activated B cells dynamically regulate the expression of complement regulatory proteins via the transcription factor BCL6. C3 convertase activity and C3aR1–C5aR1 signaling were both necessary for optimal B cell activation and germinal center formation.

Multiple myeloma disease progression and therapy response are influenced by the bone marrow niche in which the tumor cells reside. To characterize this supportive niche, Cupedo and colleagues use single-cell transcriptomic analysis of bone marrow stromal cell populations from individuals with multiple myeloma. They identify a myeloma-specific inflammatory mesenchymal stromal cell (iMSC) population that spatially colocalizes with tumor cells. Anti-myeloma induction therapy does not influence iMSC presence, suggesting a role for bone marrow inflammation in myeloma persistence or relapse.

Raychaudhuri and colleagues use high-dimensional single-cell analysis of T cells from a human tuberculosis progression cohort. They identify a T_H17–like cluster reactive to Mycobacterium tuberculosis peptides that is reduced in people who previously progressed to active disease.