End-Stage Renal Disease Causes Skewing in the TCR Vβ-Repertoire Primarily within CD8+ T Cell Subsets

Abstract

A broad T cell receptor (TCR-) repertoire is required for an effective immune response. TCR-repertoire diversity declines with age. End-stage renal disease (ESRD) patients have a prematurely aged T cell system which is associated with defective T cell-mediated immunity. Recently, we showed that ESRD may significantly skew the TCR Vβ-repertoire. Here, we assessed the impact of ESRD on the TCR Vβ-repertoire within different T cell subsets using a multiparameter flow-cytometry-based assay, controlling for effects of aging and CMV latency. Percentages of 24 different TCR Vβ-families were tested in circulating naive and memory T cell subsets of 10 ESRD patients and 10 age- and CMV-serostatus-matched healthy individuals (HI). The Gini-index, a parameter used in economics to describe the distribution of income, was calculated to determine the extent of skewing at the subset level taking into account frequencies of all 24 TCR Vβ-families. In addition, using HI as reference population, the differential impact of ESRD was assessed on clonal expansion at the level of an individual TCR Vβ-family. CD8⁺, but not CD4⁺, T cell differentiation was associated with higher Gini-TCR indices. Gini-TCR indices were already significantly higher for different CD8⁺ memory T cell subsets of younger ESRD patients compared to their age-matched HI. ESRD induced expansions of not one TCR Vβ-family in particular and expansions were predominantly observed within the CD8⁺ T cell compartment. All ESRD patients had expanded TCR Vβ-families within total CD8⁺ T cells and the median (IQ range) number of expanded TCR Vβ-families/patient amounted to 2 (1-4). Interestingly, ESRD also induced clonal expansions of TCR Vβ-families within naive CD8⁺ T cells as 8 out of 10 patients had expanded TCR Vβ-families. The median (IQ range) number of expanded families/patient amounted to 1 (1-1) within naive CD8⁺ T cells. In conclusion, loss of renal function skews the TCR Vβ-repertoire already in younger patients by inducing expansions of different TCR Vβ-families within the various T cell subsets, primarily affecting the CD8⁺ T cell compartment. This skewed TCR Vβ-repertoire may be associated with a less broad and diverse T cell-mediated immunity.

Keywords: CMV-latency; T cell subsets; TCR-repertoire; ageing (aging); end-stage renal disease.

Figure 1

Gini-T cell receptor (TCR) indices for different T cell subsets. The different Gini-TCR indices are depicted for healthy individual (HI) (A,C,E,G) and end-stage renal disease (ESRD) patients (B,D,F,H). First, the Gini-TCR indices for recent thymic emigrant (CD31⁺ naive) and CD31⁻ naive CD4⁺ (A,B) and CD8⁺ T (C,D) cells are given, respectively. Next, the differentiation-associated effects on Gini-TCR indices are depicted for CD4⁺ (E,F) and CD8⁺ (G,H) T cell subsets, including naive, central memory, effector memory, and terminally differentiated effector memory CD45RA⁺ (EMRA) T cells. *, **, and *** reflect P-values <0.05, 0.01, and 0.001, respectively. Data from 10 HI and 10 ESRD patients are given as median with interquartile range.

Figure 2

Effect of end-stage renal disease (ESRD) on Gini-T cell receptor (TCR) indices of CD8⁺ T cell subsets. In (A), the median and IQ range of the Gini-TCR indices for healthy individuals (N = 10) and ESRD patients (N = 10) for different CD8⁺ T cell subsets is depicted, whereas in (B,C) those for the younger and older group (N = 5) are given, respectively. P value: *<0.05.

Figure 3

Expansions of T cell receptor (TCR) Vβ-families within CD8⁺ memory T cells from end-stage renal disease (ESRD) patients. Boxes and error bars represent the mean and 95% confidence interval (mean ± 2SD) of 24 TCR-Vβ families from 10 healthy individuals (HI). Red dots correspond to expanded TCR Vβ-families from ESRD patients (frequencies > mean + 2SD from HI).

Figure 4

End-stage renal disease effect on T cell receptor (TCR) Vβ-families within T cell subsets. Using healthy individual (HI) (N = 10) as a reference population, we evaluated the number of TCR Vβ-families that were expanded per patient for a T cell subset (frequency of a TCR Vβ-family exceeding the mean + 2SD value obtained for HI) (A). In (B,C), the median (IQ range) of expansions per younger and older patient for a T cell subset is depicted using the younger (N = 5) and older HI (N = 5) as a reference, respectively. The open bars represent the median and IQ range for the different CD4⁺ T cell subsets, whereas the closed bars represent that for the different CD8⁺ T cell subsets.