Amid growing investment in the field, a new paper argues it rests on shaky foundations

As technology improves, the temptation to use it to game the system grows

In vitro stimulation of healthy human immune cells is commonly used to reproduce the immune states observed in disease, both to understand pathology and to test therapeutic approaches. However, experiments typically focus on individual cell types and stimuli and a comprehensive cellular comparison of common immunomodulators and their relevance to disease is lacking. To this end, we performed integrated single-cell transcriptomic profiling of human peripheral blood mononuclear cells treated with 11 different common in vitro stimuli, totalling over 150,000 cells from 21 immune cell subtypes. Comparative analysis of the immunomodulations revealed their shared and unique pathways, for instance stimulation via the T cell receptor (anti-CD3, CytoStimTM) and IFN-α induced broad activation signatures including off-target effects across multiple cell types, whereas TNF-α and LPS elicited more specific responses. Ligand-receptor interaction mapping also uncovered the common and distinct intercellular signalling pathways across stimuli. Comparing the stimuli to patient samples enabled identification of specific inflammatory disease features best replicated by each. For example, IFN-α stimulation recapitulated signatures of SLE across cell types, whereas LPS induced SLE-like changes specifically within monocytes. Comparative cell-cell network analysis showed that in vitro stimuli were able to recreate some, but not all, aspects of intercellular interactions upregulated in SLE, highlighting the limitations of these model systems. This resource provides new insights into the similarities and differences of established immune stimuli at cellular resolution and facilitates appropriate use of in vitro systems to study pathways relevant to disease. ### Competing Interest Statement The authors have declared no competing interest.

Hidradenitis suppurativa is a skin condition that causes painful abscesses in skin folds. There are three stages of the disease. A new clinical trial, ABCESS2, has recently been launched to treat stag...

Lawsuit signifies dramatic escalation of battle between administration and Harvard

A free online humanities course about how to learn and work and thrive in an AI world.

Prof Maria Leptin rejects view ‘this is a big opportunity to snatch back our colleagues’

Researchers say woman treated for neuroblastoma as a child is longest known survivor after having CAR T-cell therapy A woman treated with a pioneering type of immunotherapy for a solid tumour has been in remission for more than 18 years with no further…

How does the genome encode the form of the organism? What is the nature of this genomic code? Inspired by recent work in machine learning and neuroscience, we propose that the genome encodes a generat...

Microglia are proposed to have a role in brain development through synaptic engulfment and paracrine signaling. O’Keeffe et al. show that certain neurodevelopmental processes attributed to microglia c...

Impaired mitochondrial bioenergetics in macrophages can drive hyperinflammatory cytokine responses, but whether this may also be caused by inherited mtDNA mutations is unknown. Here, we address this q...