CD45RC Isoform Expression Identifies Functionally Distinct T Cell Subsets Differentially Distributed between Healthy Individuals and AAV Patients

Laurence Ordonez,Jan Damoiseaux,Jan Willem Cohen Tervaert,Fatima-Ezzahra L'Faqihi-Olive,Isabelle Bernard,Abdelhadi Saoudi,Johan K Sandberg

doi:10.1371/journal.pone.0005287

Abstract

In animal models of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), the proportion of CD45RC T cell subsets is important for disease susceptibility. Their human counterparts are, however, functionally ill defined. In this report, we studied their distribution in healthy controls (HC), AAV patients and in Systemic lupus erythematous (SLE) patients as disease controls. We showed that CD45RC expression level on human CD4 and CD8 T cells identifies subsets that are highly variable among individuals. Interestingly, AAV patients exhibit an increased proportion of CD45RClow CD4 T cells as compared to HC and SLE patients. This increase is stable over time and independent of AAV subtype, ANCA specificity, disease duration, or number of relapses. We also analyzed the cytokine profile of purified CD4 and CD8 CD45RC T cell subsets from HC, after stimulation with anti-CD3 and anti-CD28 mAbs. The CD45RC subsets exhibit different cytokine profiles. Type-1 cytokines (IL-2, IFN-γ and TNF-α) were produced by all CD45RC T cell subsets, while the production of IL-17, type-2 (IL-4, IL-5) and regulatory (IL-10) cytokines was restricted to the CD45RClow subset. In conclusion, we have shown that CD45RC expression divides human T cells in functionally distinct subsets that are imbalanced in AAV. Since this imbalance is stable over time and independent of several disease parameters, we hypothesize that this is a pre-existing immune abnormality involved in the etiology of AAV.

Highlights

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitutes a group of disorders characterized by autoimmune inflammation affecting small- to medium-sized vessels, which leads to vessel occlusion and systemic organ damage [1]
We showed that the observed heterogeneity in the CD45RC subsets was not the result of different numbers of activated T cells, since we found no correlation between the proportion of CD45RC T cell subsets and the percentage of HLADR+ cells for CD4 T cells and CD8 T cells
These data demonstrate that CD45RC expression identifies different subsets of CD4 and CD8 T cells that are differentially distributed between healthy individuals independently of age or size and activation state of the T cell compartment

Summary

Introduction

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitutes a group of disorders characterized by autoimmune inflammation affecting small- to medium-sized vessels, which leads to vessel occlusion and systemic organ damage [1]. Brown Norway (BN) rats, that are prone to develop MPO-ANCA associated vasculitis [26,27,28,29], have a preponderance of the CD45RClow T cell subset [25] This difference in the proportion of CD45RChigh and CD45RClow T cell subsets is genetically controlled by the same chromosomal regions that have been shown to influence the susceptibility to immune mediated disorders [22,23,25,30]. Based on these experimental findings, suggesting that the imbalance between CD45RChigh and CD45RClow T cell populations contributes to the susceptibility to vasculitis, we examined the distribution and function of the CD45RC subsets in healthy individuals and AAV patients

Methods

Results

Conclusion