T Cell Repertoire Diversity After Umbilical Cord Transplant Predicts Mortality From Infection

In a transplant study run at Fred Hutchinson Cancer Research Center, 34 patients with high risk hematological malignancies underwent a myeloablative procedure and were subsequently transplanted with double umbilical cord blood units. Peripheral blood samples were collected from each patient before myeloablation, and at 28, 56, 100, 180, and 360 days post-transplant.

At each time point, we used the immunoSEQ platform to perform high-throughput sequencing of rearranged T Cell Receptor (TCR) loci. Using immunoSEQ data, we were able to track the presence and frequency of individual TCR clones in each patient across time-points, as well as measuring the diversity of the TCR repertoire as a whole. We correlated our measure of TCR repertoire diversity with clinical outcomes in this cohort.

The study produced two primary results. First, using the ability to track clones, the reconstituting TCR repertoire is shown to oscillate wildly with nearly complete turnover of the T cell repertoire occurring at least monthly after CB transplant. The largest T cell clones present in each blood draw drop below detection within weeks, contrasting with control data in which the top clones in healthy patients are not only observed in multiple subsequent time-points, but remain at high frequency. The second result is a test of the hypothesis that diversity of the T cell repertoire is a measure of immunocompetence, as a clinical application of high-throughput sequencing. Of the 34 patients, six died between Day 100 and Day 360 of non-relapse causes. At both Day 56 and Day 100, the diversity of the T cell repertoires of those six patients were far lower than the T cell repertoire diversity values of the remaining patients (P-value = 0.015).

We have demonstrated that the reconstitution of clinical immunity in cord blood transplantation patients is characterized by a highly unstable T cell compartment with very rapid turnover of T cell clones. Despite the transience of individual T cell clones, however, by two months after transplant T cell repertoire diversity as measured by high-throughput TCR sequencing accurately predicts risk of non-relapse mortality.

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