Dysregulation of IL-2/IL-2R system alters proliferation of early activated CD4+ T cell subset in patients with end-stage renal failure.
OBJECTIVE
Although CD4+ T cells are preactivated in patients with end-stage renal failure (ESRF), these patients present an impairment of T cell immune response, which is partly responsible for the higher incidence of infection in this population. The aim of the present study was to analyze the mechanisms underlying the altered function of activated CD4+ T cells in patients with ESRF.


METHODS
Thirty patients undergoing chronic hemodialysis (HD) and 20 patients with ESRF were compared with 15 sex- and age-matched controls. CD4+ T cell early activation (CD69, CD25), interleukin-2 (IL-2)/IL-2 receptor (IL-2R) system, and proliferation capacity of CD69+/CD4+ T cells were assessed ex vivo after blood draw sampling, in culture conditions and after phytohemagglutinin (PHA) stimulation.


RESULTS
Although the CD4+ T cell count was lower in chronic HD patients than in predialysis patients and controls (p = 0.007), CD4+ T cells showed a pre-activation state as demonstrated by higher percentage of CD69+/CD4+ T cells and CD25+/CD4+ T cells in chronic HD patients compared with the other groups ex vivo. Furthermore, CD69+/CD4+ T cells from chronic HD patients spontaneously released more IL-2 (22 +/- 6 pg/ml) than those from pre-dialysis patients (12 +/- 4 pg/ml, p = 0.005) and controls (5 +/- 3 pg/ml, p = 0.001). However, after PHA stimulation, CD69+/CD4+ T cells from chronic HD patients expressed lower cell surface CD25 density, and were unable to show further activation. Indeed, these cells produced less IL-2 and released more soluble IL-2R, and correlatively with IL-2 production, they showed lower proliferation capacity compared with predialysis patients (p = 0.001) and controls (p < 0.001). They also displayed decreased responsiveness to exogenous human recombinant IL-2. The restoration of the PHA stimulation index of CD69+/CD4+ T cells from chronic HD patients in the presence of normal human serum as well as the decreased stimulation index of CD69+/CD4+ T cells from control subjects incubated with HD serum, strongly suggest that uremic toxins and mediators induced by HD affect the IL-2/IL-2R pathway.


CONCLUSIONS
These findings demonstrate the presence, in chronic HD patients, and to lesser extent, in predialysis patients, of abnormally high proportion of spontaneously preactivated CD4+ T cells whose proliferation and further activation are blunted due to dysregulation of the IL-2/IL-2R system.
Meier
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P
Division of Nephrology, Department of Medicine, Hôpital de Sion, Switzerland. Pascal.Meier@chuv.hospvd.ch
Dayer
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E
Ronco
P
P
Blanc
E
E
D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000032:analysis / Q000502:physiology*; D007676:Kidney Failure, Chronic / Q000276:immunology*; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010835:Phytohemagglutinins / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000032:analysis / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D007376:Interleukin-2; D037181:Lectins, C-Type; D010835:Phytohemagglutinins; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D000099192:CD69 Antigens