T cell tolerant fraction as a predictor of graft-vs-host disease following allogeneic hematopoietic cell transplantation

Background

Donor T cell reconstitution following allogeneic hematopoietic cell transplantation (HCT) is crucial for protective immunity against infections and cancer relapse. However, its use remains limited by the risk of graft-versus-host disease (GvHD), a serious complication arising when donor T cells target recipient tissues. Here we evaluate a novel metric—the T cell receptor beta (TRB) tolerant fraction—as a predictor of GvHD risk.

Methods

We analyzed TRB sequencing data from mouse models of GvHD and pre-transplantation samples from previously published human HCT studies. We computed the TRB tolerant fraction based on the overlap between baseline (pre-conditioning) donor and recipient TRB repertoires and assessed its ability to predict acute and chronic GvHD.

Results

In mice, a common donor-recipient pairing (DRP) known to induce severe acute GvHD exhibited lower TRB tolerant fractions compared to control DRP with lower risk of GVHD. In human patients, individuals who developed acute GvHD showed a trend toward lower TRB tolerant fractions compared to those who remained free of GVHD. Notably, patients developing chronic GvHD had lower TRB tolerant fractions compared to patients without chronic GvHD (p = 0.019). ROC-AUC analysis further validated predictive capability for chronic GvHD (AUC = 0.81) in the cohort examined.

Conclusions

The TRB tolerant fraction calculated from pre-transplant donor-recipient TRB sequence overlap robustly predicts chronic GvHD and may do so for acute GvHD as well. This method may enhance donor selection and personalized risk assessment strategies, providing an avenue for reducing GvHD incidence through improved T cell compatibility screening and merits further study.

Highlights

• We introduce the TRB tolerant fraction to measure of how many donor TCRβ sequences fall within a recipient’s tolerance space.

• The metric compares donor TRB sequences that overlap the recipient’s productive TRB repertoire (i.e expressed and be tolerant selected) with those overlapping the recipient’s non-productive TRB sequences (cannot express and not tolerant selected) .

• The metric is evaluated in established mouse donor–recipient pairs and in human allogeneic hematopoietic cell transplantation (allo-HCT) cohorts.

• We find the tolerant fraction shows a consistent signal associated with risk of graft-versus-host disease (a clinical sign of failed T-cell tolerance) in both mice and humans.

• The TRB tolerant fraction may add information beyond routine clinical factors.