Good news!
"... team of researchers ... have now characterized a subset of specialized T cells, V-gamma-4 (Vg4), which play a key role in gut-lining protection and repair. ...
Looking at healthy and IBD colon tissue samples from 150 patients, the researchers found a distinct difference in gamma delta (γδ) T cells between the two cohorts. In healthy guts, they found a robust population of Vg4 T cells, but in the tissue taken from IBD patients, this subset of cells was different, and in many cases significantly depleted. ...
If these protective immune cells are depleted, it leaves the gut vulnerable to disease progression. People with poorly managed IDB are at a higher risk of developing colorectal cancer. ...
The researchers also found that IBD patients who had a restored, functioning Vg4 T cell population were less likely to relapse after a bout of inflammation than those who didn’t. ..."
From the editor's note and the abstract:
"Editor’s summary
Inflammatory bowel disease (IBD) refers to two conditions, Crohn’s disease and ulcerative colitis. Individuals with IBD have chronic intestinal inflammation in which the intestinal epithelial barrier is disrupted. Dart et al. examined human colon biopsy samples and identified intestinal immune cells called Vγ4 γδ Τ lymphocytes (see the Perspective by Galipeau and Verdu). In healthy individuals, this γδ T cell subset is kept in check by intestinal epithelial cells displaying the butyrophilin-like (BTNL) proteins BTNL3 and BTNL8. By contrast, analysis of biopsies from Crohn’s disease patients revealed a polymorphism encoding a defective BTNL3:BTNL8 fusion protein, and this genetic mutation was correlated with IBD severity. These findings increase our understanding of barrier immunology and may provide new perspectives for IBD management.
Structured Abstract
INTRODUCTION
Together with B cells and αβ T cells, γδ T lymphocytes comprise a third component of adaptive immunity conserved across vertebrates. ... Such γδ lymphocytes can contribute to the maintenance of tissue homeostasis and to its restoration after injury. Thus, any conservation of this biology in humans could have profound implications for basic tissue biology and for inflammatory pathologies at barrier sites, such as inflammatory bowel disease (IBD), which comprises the relapsing and remitting conditions Crohn’s disease (CD) and ulcerative colitis (UC). In humans, Vγ4+ cells that engage heteromers of BTNL3 and BTNL8 have been identified. However, the degree to which the human intestinal γδ T cell compartment mirrors that of the mouse and the potential implications for IBD are unresolved. IBD is of increasing global prevalence, and despite treatment advances, there remain many unmet needs. Although anti-inflammatory agents may ameliorate symptoms and inflammation in some cases, they have little capacity for curative epithelial repair, added to which the field lacks reliable prognostic biomarkers of disease progression.
RATIONALE
Using mucosal samples obtained at colonoscopy from more than 150 individuals, we characterized the healthy human gut γδ T cell population. We then investigated how this compartment changes in patients with IBD and in people who carry a germline mutation in BTNL3 and BTNL8. Finally, we explored whether the status of the colonic γδ T cell compartment might be associated with remission in IBD patients on treatment.
RESULTS
We established that the human colon harbors a complex γδ T cell repertoire, within which a subcompartment comprises Vγ4+ cells coexpressing the integrin CD103, which can engage E-cadherin on epithelial cells. The CD103+Vγ4+ cells have a distinct phenotype, combining T cell and natural killer cell ligand recognition systems, but they are also noticeably recalcitrant to conventional effector activation. By contrast, these cells respond strongly to BTNL3 and BTNL8 heteromers, and although they do not dominate the γδ T cell compartment to the degree observed for counterpart murine BTNL-reactive cells, they are BTNL selected. This was illustrated by our demonstration of the cells’ loss and dysregulation in persons homozygous for a BTNL3 and BTNL8 copy number variant (CNV) allele that we showed to be severely hypomorphic. Using a case-control genetic screen, we also showed that the CNV allele is a risk modifier, predisposing CD patients to a severe, penetrating pathology. Consistent with this, the distinct CD103+Vγ4+ T cell subset is vulnerable to the impacts of IBD-associated cytokines, and Vγ4+ T cells are disproportionately depleted and dysregulated in inflamed CD and UC. Conversely, restoration of the compartment in areas of healing was associated with on-treatment remission over a sustained period.
CONCLUSION
BTNL-mediated selection is an evolutionarily conserved biology driving the emergence of intestinal γδ T cells with a distinct phenotype. The frequent depletion and dysregulation of those BTNL-selected cells in UC and CD, and the association of BTNL hypomorphism with the CD disease phenotype, points to the cells’ evolutionarily conserved roles in regulating and/or restoring tissue integrity. Thus, for a disease of increasing global incidence that is primarily treated with anti-inflammatories but remains uncurable through medical therapy, IBD may benefit from clinical modalities that restore local γδ T cell activity, thereby promoting tissue surveillance and repair. Moreover, monitoring local γδ T cell status may add a much-needed prognostic biomarker of a patient’s likelihood of disease remission versus relapse."
Conserved γδ T cell selection by BTNL proteins limits progression of human inflammatory bowel disease (no public access)
Systematic analysis of human colonic γδ T cells.
Persons with genotype A (the more common genotype) harbor T cell receptor Vγ4-expressing colonic T cells that engage epithelial BTNL3+BTNL8 heteromers and display a distinct phenotype, coexpressing CD103, FcεRIγ, and natural killer (NK) receptors. That phenotype is disrupted in IBD, but its restoration on treatment is associated with sustained remission. Persons with genotype B are hypomorphic for BTNL3+8, harbor few Vγ4+ cells with the typical phenotype, and if they develop Crohn’s disease they are predisposed to a severe disease phenotype.
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