"Diversity of Regulatory T Cells in Chronic GVHD after Allogeneic Hematopoietic Cell Transplant."
Regulatory T cells (Tregs) are natural suppressors of immune responses that play a central role in the induction of immunological tolerance. Compelling evidence suggests that Tregs can prevent or ameliorate graft versus host disease (GVHD) after hematopoietic cell transplantation (HCT) in an antigen specific fashion. Studies in animal models have suggested that deficient immune reconstitution, a central feature in chronic GVHD, in the Treg compartment may be the cause of the organ specific autoimmune manifestations in chronic GVHD. We hypothesize that decreased Treg TCR repertoire diversity is associated with the development of chronic GVHD after HCT in humans.
To date, due to the magnitude of the TCR diversity, technical limitations have prevented accurate measurements of the size and diversity of the TCR repertoire in any given lymphocyte population.
The specific aims of this project are:
(1) To conclude the development of an assay that will enable the direct sequencing and enumeration of all TCR ƒÑ [a] and ƒÒƒn [b] CDR3 regions present in any given biological sample by using high-throughput, short-read DNA sequencing,
(2) To create a relational database to store and query the sequencing data generated in specific aim 1, and
(3) To directly measure and compare the ƒÑƒÒ [ab] TCR diversity of the CD4+CD25+ Foxp3+ regulatory T cell compartment between patients with and without chronic graft versus host disease after hematopoietic cell transplant.
The current project has the potential to generate knowledge that can be applied in the design of new therapeutic interventions, aiming at the manipulation of the Treg repertoire, for chronic GVHD treatment.