Altered Responses to Homeostatic Cytokines in Patients with Idiopathic CD4 Lymphocytopenia

Florence Bugault,Ivan Landires,Daniela Benati,Jacques Thèze,Lisa A Chakrabarti,Pierre Rohrlich,Luc Mouthon,Vincent Pestre,Olivier Lortholary

doi:10.1371/journal.pone.0055570

Abstract

Idiopathic CD4 lymphocytopenia (ICL) is a rare immune deficiency characterized by a protracted CD4+ T cell loss of unknown etiology and by the occurrence of opportunistic infections similar to those seen in AIDS. We investigated whether a defect in responses to cytokines that control CD4+ T cell homeostasis could play a role in ICL. Immunophenotype and signaling responses to interleukin-7 (IL-7), IL-2, and thymic stromal lymphopoietin (TSLP) were analyzed by flow cytometry in CD4+ T cells from 15 ICL patients and 15 healthy blood donors. The induction of phospho-STAT5 after IL-7 stimulation was decreased in memory CD4+ T cells of some ICL patients, which correlated with a decreased expression of the IL-7Rα receptor chain (R = 0.74, p<0.005) and with lower CD4+ T cell counts (R = 0.69, p<0.005). IL-2 responses were also impaired, both in the Treg and conventional memory subsets. Decreased IL-2 responses correlated with decreased IL-7 responses (R = 0.75, p<0.005), pointing to combined defects that may significantly perturb CD4+ T cell homeostasis in a subset of ICL patients. Unexpectedly, responses to the IL-7-related cytokine TSLP were increased in ICL patients, while they remained barely detectable in healthy controls. TSLP responses correlated inversely with IL-7 responses (R = −0.41; p<0.05), suggesting a cross-regulation between the two cytokine systems. In conclusion, IL-7 and IL-2 signaling are impaired in ICL, which may account for the loss of CD4+ T cell homeostasis. Increased TSLP responses point to a compensatory homeostatic mechanism that may mitigate defects in γc cytokine responses.

Highlights

Idiopathic CD4+ lymphocytopenia (ICL) is an immune deficiency characterized by persistently decreased CD4+ T lymphocyte numbers in the absence of HIV infection or other known causes of T cell depletion [1,2,3,4,5,6,7,8]
We found that CD4+ T cells from ICL patients responded less efficiently to both IL-2 and IL-7
Whole blood phenotyping analyses showed a decrease in the percentage of CD45RA+ CD4+ T cell population in ICL patients as compared to healthy blood donors (Table 2; p = 0.0005)

Summary

Introduction

Idiopathic CD4+ lymphocytopenia (ICL) is an immune deficiency characterized by persistently decreased CD4+ T lymphocyte numbers in the absence of HIV infection or other known causes of T cell depletion [1,2,3,4,5,6,7,8]. Abnormal immune activation was confirmed by the detection of an increased T cell turnover [12] and by the presence of microbial translocation products in the plasma of ICL patients, similar to findings reported in HIV infection [13]. The mutations targets the adaptor protein uncoordinated 119 (UNC119), which is required for Lck transport and activation [18], or the magnesium transporter 1 (MAGT1), which contributes to the proper activation of phospholipase C gamma 1 (PLCc1) [19] It should be noted, that only a few of ICL patients show signs of impaired TCR signaling [20]

Methods

Results

Conclusion