CD38 Correlates with an Immunosuppressive Treg Phenotype in Lupus-Prone Mice.

Jocelyn C Pérez-Lara,Leopoldo Santos-Argumedo,Claudia Sandoval-Montes,Juan C Rodríguez-Alba,Fabio García-García,Gabriela López-Herrera,Enrique Espinosa,Mónica Flores-Muñoz,Héctor Romero-Ramírez,Vianney Ortiz-Navarrete

doi:10.3390/ijms222111977

Abstract

CD38 is a transmembrane glycoprotein expressed by T-cells. It has been reported that patients with systemic lupus erythematosus (SLE) showed increased CD38+CD25+ T-cells correlating with immune activation and clinical signs. Contrariwise, CD38 deficiency in murine models has shown enhanced autoimmunity development. Recent studies have suggested that CD38+ regulatory T-cells are more suppressive than CD38− regulatory T-cells. Thus, we have suggested that CD38 overexpression in SLE patients could play a role in regulating immune activation cells instead of enhancing it. This study found a correlation between CD38 with FoxP3 expression and immunosuppressive molecules (CD69, IL-10, CTLA-4, and PD-1) in T-cells from lupus-prone mice (B6.MRL-Faslpr/J). Additionally, B6.MRL-Faslpr/J mice showed a decreased proportion of CD38+ Treg cells regarding wild-type mice (WT). Furthermore, Regulatory T-Cells (Treg cells) from CD38-/- mice showed impairment in expressing immunosuppressive molecules and proliferation after stimulation through the T-cell receptor (TCR). Finally, we demonstrated an increased ratio of IFN-γ/IL-10 secretion in CD38-/- splenocytes stimulated with anti-CD3 compared with the WT. Altogether, our data suggest that CD38 represents an element in maintaining activated and proliferative Treg cells. Consequently, CD38 could have a crucial role in immune tolerance, preventing SLE development through Treg cells.

Highlights

Systemic lupus erythematosus (SLE) is a chronic, multiorgan, systemic autoimmune disease that affects nearly every tissue and organ system [1]
An unprecedented number of studies performed in SLE patients have demonstrated that CD38 is widely expressed in T-cells, showing that CD25+CD38+ T-cells are increased regarding healthy controls [15,16,17,18,19]
It has been proposed that the increase in CD25+CD38+ T-cells in SLE disease could be indicative of persistent T-cell activation [19]

Summary

Introduction

Systemic lupus erythematosus (SLE) is a chronic, multiorgan, systemic autoimmune disease that affects nearly every tissue and organ system [1]. Pavón et al reported higher levels of CD38 expression in CD25+ T-cells from SLE patients than in healthy controls [19], suggesting that CD38 expression is derived from chronic immune activation correlating with disease severity. In contradiction with these previous reports, some authors have suggested that CD38 plays a role in preventing autoimmunity. CD38 was upregulated in regulatory B cells (Bregs), and CD38 cross-linking with an agonistic antibody increased the frequency of Breg cells and IL-10 production [22] It seems that the CD38 receptor can play an essential role in preventing autoimmunity mechanisms, mainly through the regulation of the immune system

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Results

Conclusion