CD4+ TEMRA Cells, Galectin-7 Linked to IPF Risk
Key Takeaways
- Among patients with IPF, peripheral-blood CD4+ TEMRA cells accounted for 1% versus 2% of T cells in controls.
- Higher genetically predicted relative CD4+ TEMRA abundance was associated with lower IPF risk in both genetic cohorts.
- Galectin-7 was detected in IPF metaplastic basal cells; donor-derived basal-cell organoids secreted it, and separate cell experiments linked galectin-7 to reduced CD4+ TEMRA differentiation.
- Neoeriocitrin reduced collagen in human IPF lung slices and fibrosis in mice, both experimental outcomes rather than demonstrated patient benefits.
Yan and colleagues examined CD4+ TEMRA cells and galectin-7 in IPF by pairing two-sample Mendelian randomization (MR) of immune traits against independent discovery and validation genome-wide association studies (GWAS) with patient blood, explanted IPF and donor lungs, single-cell and spatial profiling, flow cytometry, and regional immunofluorescence. A blood flow-cytometry comparison included five IPF patients and five controls; IPF lung tissue came from transplant patients, and patient specimens were associated with Chinese transplant centers. Flow cytometry identified CD4+ TEMRA cells by surface markers. Functional work used healthy-donor CD4+ cells, metaplastic basal-cell organoids, patient-derived precision-cut lung slices, receptor and signaling assays, and a virtual compound screen. Bleomycin-exposed mice received interleukin-7 (IL-7) or underwent lung-epithelial Lgals7 perturbation and compound-versus-vehicle testing.
Higher genetically predicted relative CD4+ TEMRA abundance among T cells was associated with lower IPF risk in the discovery MR cohort (odds ratio [OR] 0.712; 95% confidence interval [CI] 0.565–0.896) and validation cohort (OR 0.452). Separately measured patient blood showed fewer CD4+ TEMRA cells in IPF than in controls. Independent blood single-cell data and lung profiling also supported lower abundance, without establishing that administering these cells would prevent IPF.
Regional immunofluorescence found CD4+ TEMRA infiltration of 4.5% in more fibrotic lower versus 22% in less affected upper IPF lung regions; a TEMRA-differentiation signature also varied inversely with actin alpha 2, smooth muscle (ACTA2). Human IPF tissue showed galectin-7 in keratin 5-positive metaplastic basal cells, and organoids secreted it. In perturbation assays, galectin-7 pretreatment reduced IL-7-Fc binding to CD4+ T cells, consistent with competition for receptor binding; galectin-7 reduced signal transducer and activator of transcription 5 (STAT5) and Janus kinase 1 (JAK1) phosphorylation and inhibited TEMRA differentiation. IL-7-induced TEMRA cells reduced collagen in IPF lung slices relative to naive CD4+ cells; IL-7 reduced severe injury in bleomycin-exposed mice, whereas lung-epithelial Lgals7 overexpression reduced mouse TEMRA frequency and increased fibrosis. Neoeriocitrin, identified through screening, yielded approximately 73% less collagen staining than control in patient-derived IPF lung slices. Thermophoresis and thermal-shift assays supported galectin-7 binding; cultured cells showed partial restoration of suppressed STAT5/JAK1 phosphorylation, and Lgals7-overexpressing mice had less fibrosis with neoeriocitrin than with vehicle.
Genetic causal-inference estimates, patient specimen associations, cultured-cell assays, human tissue outside the body, and bleomycin mouse experiments address different questions; none demonstrates safe or effective patient treatment through TEMRA-cell augmentation, galectin-7 targeting, or neoeriocitrin. The authors noted limited tissue availability for some organoid and lung-slice experiments, the imperfect resemblance of bleomycin injury to chronic IPF and modest Lgals7 induction in that model, and possible neoeriocitrin actions beyond galectin-7.
Yan and colleagues linked the observed CD4+ TEMRA pattern to a proposed epithelial galectin-7/IL-7 signaling axis and nominated neoeriocitrin for further experimental assessment. Pharmacokinetic, toxicity, and efficacy work remains necessary before clinical translation; patient treatment efficacy and intervention safety were not established.
Clinician Questions
Which ancestry groups were represented in the CD4+ TEMRA–IPF genetic analysis?
The genetic summary data relating relative CD4+ TEMRA abundance to IPF risk came entirely from populations of European ancestry. Patient blood and explanted lung measurements were separate from those GWAS data, so the genetic estimates do not establish equivalent associations in other ancestry groups.
How were CD4+ TEMRA cells identified by flow cytometry in patients with IPF?
For blood and lung comparisons involving IPF, investigators defined CD4+ TEMRA cells as live/CD45+/CD3+/CD4+/CD45RA+/CCR7− cells by flow cytometry. This marker combination specified the measured cell population, not an antifibrotic effect by itself.