Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation.

Simona Pagliuca,Cassandra M Kerr,Sanghee Hong,Betty K Hamilton,Navneet S Majhail,Yihong Guan,Ran Zhao,Hassan Awada,Jaroslaw P Maciejewski,Ashwin Kishtagari,Babal K Jha,Valeria Visconte,Hetty E Carraway,Sunisa Kongkiatkamon,Laila Terkawi,Thomas Laframboise,Misam Zawit,Bhumika J Patel,Carmelo Gurnari

doi:10.1172/jci.insight.149080

Abstract

TCR repertoire diversification constitutes a foundation for successful immune reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT). Deep TCR Vβ sequencing of 135 serial specimens from a cohort of 35 allo-HCT recipients/donors was performed to dissect posttransplant TCR architecture and dynamics. Paired analysis of clonotypic repertoires showed a minimal overlap with donor expansions. Rarefied and hyperexpanded clonotypic patterns were hallmarks of T cell reconstitution and influenced clinical outcomes. Donor and pretransplant TCR diversity as well as divergence of class I human leukocyte antigen genotypes were major predictors of recipient TCR repertoire recovery. Complementary determining region 3–based specificity spectrum analysis indicated a predominant expansion of pathogen- and tumor-associated clonotypes in the late post–allo-HCT phase, while autoreactive clones were more expanded in the case of graft-versus-host disease occurrence. These findings shed light on post–allo-HCT adaptive immune reconstitution processes and possibly help in tracking alloreactive responses.

Highlights

The success of allogeneic hematopoietic cell transplantation strictly depends on the ability of a donor’s engrafted immune system to both secure effective graft-versus-leukemia (GvL) responses and overcome infectious complications resulting from transplant-related immunodeficiency
We found that donor and recipient pre-HCT Inverse Simpson Index (ISI) were predictive of a broader TCR repertoire diversity in both early and late time points post-HCT (P < 0.0001), while T cell content in the graft, intensity of conditioning regimen, graft source, T cell depletion, type of donor, and donor/recipient CMV status did not affect any of those parameters (Figure 3, A and B)
A delayed and/or functionally impaired T cell immune reconstitution is a crucial determinant of clinical outcomes following HCT [10, 27]

Summary

Introduction

The success of allogeneic hematopoietic cell transplantation (allo-HCT) strictly depends on the ability of a donor’s engrafted immune system to both secure effective graft-versus-leukemia (GvL) responses and overcome infectious complications resulting from transplant-related immunodeficiency. If the recovery of innate immunity is a relatively fast process, mainly occurring within the early posttransplant phase, the adaptive immune reconstitution requires the accomplishment of a cascade of events characterized by both thymus-independent expansion of T cells infused with the graft and thymus-dependent expansion of naive T cells derived from donor hematopoietic stem cells [4,5,6,7,8]. TCR diversity is the result of a stochastic process involving rearrangements of the V(D)J segments within the TRA, TRB, TRD, and TRG genes [12], which, along with junctional hypermutability, have a theoretical potential to generate up to 1018 complementary determining region (CDR) sequences [13]. CDR3 amino acid sequences can unambiguously mark TCRβ clonotypes as natural barcodes of individual

Objectives

Methods

Results

Conclusion