Narrowing of T‐cell receptor beta variable repertoire during symptomatic herpesvirus infection in transplant patients

Abstract

Primary infection or recrudescence of latent virus infection in transplant recipients can be manifested either as asymptomatic or symptomatic disease. Here we show that symptomatic human cytomegalovirus (HCMV) or Epstein-Barr virus (EBV) infection or recrudescence following solid organ transplantation (SOT) was coincident with a dramatic skewing of T-cell receptor beta variable (TRBV) repertoire, with expansions of monoclonal/oligoclonal clonotypes. As the clinical symptoms resolved, the peripheral blood repertoire reverted to a more diverse distribution. In contrast, SOT recipients with asymptomatic or no viral infection or recrudescence showed minimal or no skewing of the T-cell receptor repertoire to maintain peripheral blood repertoire diversity. More importantly, we show that large monoclonal/oligoclonal repertoire expansions are associated with the loss of HCMV-specific T-cell function observed in SOT patients undergoing symptomatic viral infection or recrudescence, whereas SOT recipients who maintain peripheral blood TRBV repertoire diversity and functional antigen-specific T-cell responses can resist clinical symptomatic disease in spite of high levels of viral load.

Identification of errors introduced during high throughput sequencing of the T cell receptor repertoire

“…However, clonal frequencies may vary dramatically depending on a cell's specificity and immunologic history. In the setting of infection and immunity oligoclonal expansions may comprise a substantial proportion of the T cell population [5,6]. Analyses of the TCR repertoire have provided insight into the nature and dynamics of these immune responses [7-11].…”

Advances in Direct T-Cell Alloreactivity: Function, Avidity, Biophysics and Structure

“…In healthy individuals, EBV and CMV-specific tetramer frequencies can range from 10% to 40% of the total CD8 + T-cell repertoire (81). In general, as the magnitude of the memory response increases, clonality decreases and these virus specific T-cell populations tend to exhibit highly focused TCR repertoires (82)(83)(84)(85)(86). There is now increasing evidence to indicate that these extremely large, virus-specific T-cell populations have significant allospecific footprints.…”

TCR Spectratyping in Transplantation

“…Therefore, a skewed TCR repertoire will occur on reactivated viral infections. 3 It is worth noting that skewing of the TCR repertoire is not correlated with viral loads. 3 However, assaying the TCR repertoire will not allow distinguishing rejections of allografts from reactivated virus infections.…”

“…3 It is worth noting that skewing of the TCR repertoire is not correlated with viral loads. 3 However, assaying the TCR repertoire will not allow distinguishing rejections of allografts from reactivated virus infections. A non-Gaussian distribution and limited number of peaks can also indicate GvHD or graft rejection.…”

“…However, Vβ-spectratyping a polymerase chain reaction (PCR)-based technique to test the diversity of the T-cell pool, flow cytometric analysis of T cell receptor (TCR) β-chain distribution, and frequency are potential novel approaches to tackle these issues. [1][2][3][4] The TCR diversity is achieved in a 2-step process. Initially, TCR receptor genes scattered across its locus [A] are rearranged to generate a continuous open-reading frame.…”