Evolution and Clinical Implications of the T Cell Repertoire Following Cord Blood Transplant

Cord blood transplant (CBT) recipients are at increased risk of transplant related mortality, in part due to delayed hematopoietic and immune system recovery resulting in increased infectious complications. However, without direct clinical measures of immunocompetence, the specific role of delayed immunity on CBT outcomes is not easily determined and intervention studies not possible.

Blood samples were collected (pre-transplant and at days 28, 56, 100, 180 and 365 post-transplant) in 34 consecutive patients undergoing myeloablative CBT for treatment of hematologic malignancies.  All samples were subjected to Immunoseq, a novel T cell receptor (TCR) sequencing assay that delivers an unprecedented depth of sequencing data. From these data, clonal expansion and contraction of hundreds of thousands of clones were tracked over time and TCR diversity was directly measured. Basic clinical outcomes for all patients were also determined, including GvHD, overall survival, disease free survival, regimen related toxicities and infectious complications.

The ability to track clones demonstrated tremendous oscillation, with an almost entirely new T cell repertoire appearing at least monthly in CBT recipients. Furthermore, in contrast to healthy controls whose blood was sampled on a similar time-course, where the most frequent T cell clone at one time point remains the top clone at subsequent time points, the largest clones observed early post-transplant in CBT recipients subsequently dropped below detection within weeks of direct measurement. Of the 34 patients studied, six died of infectious complications between day 100 and one year. Notably, TCR diversity values for these six patients were far lower than those of the remaining patients (P-value = 0.015, see figure). 

The TCR repertoire is exceptionally dynamic following CBT, with many T cell clones rising to high frequency and then receding to an undetectably low level in a matter of weeks.  By two months after transplant, TCR diversity accurately predicted risk of death due to infection in this patient cohort, suggesting that diversity of the TCR is a direct measure of immunocompetence and may be useful as a test to guide clinical decision making in patients with acquired or congenital immunosuppression.