Analysis of the peripheral T‐cell repertoire in kidney transplant patients

Abstract

The long-term stability of renal grafts depends on the absence of chronic rejection. As T cells play a key role in rejection processes, analyzing the T-cell repertoire may be useful for understanding graft function outcomes. We have therefore investigated the power of a new statistical tool, used to analyze the peripheral blood TCR repertoire, for determining immunological differences in a group of 229 stable renal transplant patients undergoing immunosuppression. Despite selecting the patients according to stringent criteria, the patients displayed heterogeneous T-cell repertoire usage, ranging from unbiased to highly selected TCR repertoires; a skewed TCR repertoire correlating with an increase in the CD8 1 /CD4 1 T-cell ratio. T-cell repertoire patterns were compared in patients with clinically opposing outcomes i.e. stable drug-free operationally tolerant recipients and patients with the ''suspicious'' form of humoral chronic rejection and were found significantly different, from polyclonal to highly selected TCR repertoires, respectively. Moreover, a selected TCR repertoire was found to positively correlate with the Banff score grade. Collectively, these data suggest that TCR repertoire categorization might be included in the calculation of a composite score for the follow-up of patients after kidney transplantation. 3280 IntroductionTo prevent graft rejection following kidney transplantation, recipients take lifelong immunosuppression. Despite continuous improvements in such treatments, the half-life of a kidney graft has not increased significantly in the past two decades [1]. Manifest by a decrease in renal function that is associated with specific histological lesions [2], chronic rejection remains the major problem of late allograft loss [3]. The identification of biomarkers predictive of chronic rejection in patients with a stable graft function would therefore be a valuable tool in patient management [4][5][6]. In contrast to the patients who develop chronic rejection, rare cases exist of kidney recipients who tolerate their graft despite discontinuation of immunosuppression [7].Operational tolerance and suspicious chronic Ab-mediated rejection are clinical and immunological situations, representing the two opposing endpoints for patients with stable kidney graft function. Indeed, because T cells have been shown to be involved in both chronic rejection and tolerance [8], we have explored the T-cell repertoire in a cohort of patients with stable kidney graft function. We have previously shown, in a small cohort of patients, that both drug-free operationally tolerant patients (TOL patients) and patients with the ''suspicious'' form of chronic rejection (CHR patients) display a TCR repertoire that differs from healthy, nontransplanted individuals [9][10][11]. In this article, we revisit the relationship between peripheral T-cell repertoire and clinical status, using a new statistical method to analyze the TCR repertoires presented as TcLandscape (TcL) data. We show that, despite being selected accordin...

Harnessing the diversity of the human T‐cell repertoire: A monitoring tool for transplantation tolerance?

“…Using this assay, it was previously demonstrated that drug-free, operationally tolerant kidney transplant recipients have distinct gene expression changes and a distinct TCR repertoire distribution as compared with patients with chronic graft dysfunction [14]. Miqueu et al [13] build on this observation and introduce time-tested and adapted statistical approaches [15] to investigate the TCR repertoire distribution, and validate the earlier findings in a much larger patient cohort. Miqueu et al [13] found that the operationally tolerant kidney allograft recipients have a TCR repertoire distribution that resembles the distribution of healthy volunteers (a Gaussian-like distribution or only mild Kurtosis -peakednessof the distribution of the TcLandscape s in all), with a Gaussianlike distribution pattern or a pattern with only mild Kurtosis in 93% of tolerant patients, compared with 43% of patients with chronic humoral rejection [13].…”

“…Miqueu et al [13], in this issue of the European Journal of Immunology, report on a large, multicenter, case-controlled study, to evaluate the TCR repertoire with 'TcLandscape s ', which combines CDR3-LD analysis with qPCR of Vb transcripts, to answer this question. Using this assay, it was previously demonstrated that drug-free, operationally tolerant kidney transplant recipients have distinct gene expression changes and a distinct TCR repertoire distribution as compared with patients with chronic graft dysfunction [14].…”

Expansion of Highly Differentiated Cytotoxic Terminally Differentiated Effector Memory CD8+ T Cells in a Subset of Clinically Stable Kidney Transplant Recipients

“…[9][10][11] Similar observations made in the blood of CAMR patients reported a restricted TCR Vb repertoire, an increase in IFN-g, GZM-B, and perforin-1 (PERF-1) transcripts, and an increase in CD8 T cells. [12][13][14] These observations suggest that alteration in the TCR Vb repertoire of CD8 T cells may be associated with kidney dysfunction. We previously reported that different shapes of TCR Vb repertoire are identified in patients with stable graft function, despite the stringent clinical criteria used to constitute a homogeneous group.…”

“…TCR Vb repertoires were stratified into diverse and restricted profiles using the rules recently developed. 14 …”

“…We previously reported that different shapes of TCR Vb repertoire are identified in patients with stable graft function, despite the stringent clinical criteria used to constitute a homogeneous group. 14 In this prospective study, we examined CD8 T-cell phenotype and function and the long-term clinical outcome of these patients with stable graft function (n=131) who exhibit different usage of their TCR Vb repertoire. We found that the restriction of the TCR Vb repertoire diversity is associated with an increase of highly differentiated terminally differentiated effector memory (TEMRA; CD45RA + CCR7…”