CMV reactivation drives post-transplant T cell reconstitution and results in defects in the underlying TCRβ repertoire.

Publication Type:

Journal Article

Source:

Blood (2015)

Abstract:

Although CMV reactivation has long been implicated in post-transplant immune dysfunction, the molecular mechanisms that drive this phenomenon remain undetermined. To address this, we combined multiparameter flow cytometric analysis and T cell subpopulation sorting with high-throughput sequencing of the T cell repertoire, to produce a thorough evaluation of the impact of CMV reactivation on T cell reconstitution after unrelated-donor HSCT. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme B(high)/CD28(low)/CD57(high)/CD8+ effector-memory T cells and resulted in a linked contraction of all naïve T cells, including CD31+/CD4+ putative thymic emigrants. TCRβ deep sequencing revealed a striking contraction of CD8+ Tem diversity due to CMV-specific clonal expansions in reactivating patients. In addition to querying the topography of the expanding CMV-specific T cell clones, deep sequencing allowed us, for the first time, to exhaustively evaluate the underlying TCR repertoire. Our results reveal new evidence for significant defects in the underlying CD8 Tem TCR repertoire in patients who reactivate CMV, providing the first molecular evidence that in addition to driving expansion of virus-specific cells, CMV reactivation has a detrimental impact on the integrity and heterogeneity of the rest of the T cell repertoire. Registered to www.Clinicaltrials.gov as #NCT01012492.