Progressive loss of renal function is associated with activation and depletion of naive T lymphocytes

Abstract

We hypothesized that progressive loss of renal function specifically affects certain T cell subsets. T lymphocyte subsets of patients with chronic kidney disease and healthy controls were characterized by flow cytometry using heparin-anticoagulated whole blood samples. Plasma interleukin (IL)-7 and IL-15 concentrations were determined as these cytokines are critically involved in T cell homeostasis. The results revealed that a progressive decrease in renal function is associated with activation and selective loss of naive T cells and CD4⁺ central memory cells and a marked increase in CD8⁺ memory T cells that lack CD45RO and CCR7. The profile of T cell subsets of patients with CKD 5 with or without hemodialysis treatment was similar except for a pronounced shift to Th1 cells in hemodialysis patients. IL-7 but not IL-15 plasma concentrations were lowered in patients with end-stage renal disease as compared to healthy controls.

Introduction

Progression of chronic kidney disease (CKD) is associated with activation of the immune system [1]. Paradoxically, patients with end-stage renal disease (ESRD) show clinical signs of an immune defect characterized by an increased susceptibility for infections and a decreased response to hepatitis B vaccination. The precise mechanism responsible for this immune defect is unknown. However, changes in T cell function may contribute substantially to the impaired cellular immune response as ESRD is associated with lymphopenia occurring in the B and T lymphocyte compartment [2], [3], [4]. This may be caused by increased apoptosis induced by activation of T lymphocytes [5], [6]. In addition, shifts in type-1/type-2 cytokine production [7], [8] and CD4/CD8 ratio [9], [10] have been described.

There are no data on the stage of CKD in relation to the cell numbers and phenotype of specific T cell subsets. Recent developments in T cell research and the availability of various chemokine receptors, in particular CCR7, have enabled a more accurate dissection of the different T cell subsets. CCR7, a chemokine receptor important for homing to lymphoid tissue, is constitutively expressed on naive T lymphocytes. In addition, two different populations within the memory (CD45RO⁺) pool of T lymphocytes can be distinguished, i.e. a central memory population (Tcm) expressing CCR7 and an effector memory population (Tem) negative for this homing receptor [11]. Naive T lymphocytes are able to travel to secondary lymphoid organs where they encounter antigens presented by dendritic cells. Priming of these naive T lymphocytes will generate effector cells that are able to travel to inflamed tissues. However, a part of these primed cells will persist as circulating memory cells that upon secondary challenge respond more vigorously and are able to either display immediate effector function in inflamed tissues (effector memory) or constitute to a pool of long-lived memory cells that develop more quickly into effector cells following antigenic stimulation in lymphoid organs (central memory or reactive memory). Within the CD8⁺ T lymphocyte population, an extra effector memory subset can be discriminated based on the absence of both CCR7 and the memory T cell marker CD45RO (Temra). These Temra cells possess high effector function and usually occur late in the immune response in patients suffering from viral infections [12].

A further refinement of these different T cell subsets may be performed using chemokine receptors specific for type-1 or type-2 cytokine producing T lymphocytes [13] and/or activation markers like CD25 and CD27.

We hypothesized that progression of chronic kidney disease is associated with changes in specific T cell subsets, thereby explaining the uremia-associated immune defect. Therefore, the profile of the various T cell subsets was related to the stage of CKD and compared to healthy controls and patients receiving chronic intermittent hemodialysis (CIHD).