Ectonucleotidase CD38 Demarcates Regulatory, Memory-Like CD8+ T Cells with IFN-γ-Mediated Suppressor Activities

Rajia Bahri,Zane Orinska,Thomas Bollinger,Silvia Bulfone-Paus,Annalena Bollinger,Kim J Hasenkrug

doi:10.1371/journal.pone.0045234

Abstract

Regulatory CD8+ T cells are critical for self-tolerance and restricting excessive immune responses. The variety of immune functions they fulfill, the heterogeneity of their phenotype, and the mechanism of action are still poorly understood. Here we describe that regulatory CD8+ T cells exhibiting immunosuppressive actions in vitro and in vivo are recognized as CD38high T cells and present in naive mice. CD38 is a glycosylated membrane protein with ectonucleotidase properties. CD8+CD38high (CD44+CD122+CD62Lhigh) lymphocytes suppress CD4+ effector T-cell proliferation in an antigen-non specific manner via IFN-γ. While direct cell-to-cell contact is needed for this suppressor activity, it is independent of membrane-bound TGF-β and granzyme B release. IL-15 potentiates the suppressive activity of CD8+CD38high T cells and controls their survival and expansion. In humans CD8+CD38high T cells inhibit CD4+ effector T cell proliferation. In vivo, CD8+CD38high, but not CD8+CD38− T cells mitigate murine experimental autoimmune encephalomyelitis (EAE) by reducing the clinical score and delaying disease occurrence. EAE suppression is enhanced by pre-treatment of CD8+CD38high T cells with IL-15. These findings add evidence that the expression of ectoenzyme receptor family members positively correlates with suppressor functions and identifies CD8+CD38high T cells as potential inhibitors of excessive immune responses.

Highlights

We compared the phenotype of these cells to CD8+CD382 T cells using a panel of markers for T cell activation and memory function, cytokine receptors and natural killer cell (NK) markers
High levels of CD38 expression correlate with high CD122 and CD44 and low CD103 expression (Figure 1B)
We establish that CD8+CD44+CD122+CD62Lhigh T cells which are CD38high represent a distinct regulatory T cell population

Summary

Introduction

‘‘Memory-like’’ regulatory CD8+ T cells have witnessed a renaissance as suppressive immunoregulators in pathologies such as autoimmune and infectious diseases and cancer [1,2,3]. CD8+CD282 Tregs, induced in vitro by antigen stimulation, express classical regulatory markers such as Foxp, GITR, CTLA-4, CD25, CD103, CD62L and 41BB [8] and produce the immunosuppressive cytokines IL-10 and TGF-b [2,9]. Their suppressive activities are MHC class Irestricted, contact-dependent and require the presence of antigen presenting cells. Unimmunized young mice generate and maintain ‘‘memorylike’’ CD8+ T cells of unknown antigen encounter history Their immune functions, the heterogeneity of their phenotype and the mechanisms of action are still poorly understood. We propose that CD8+CD38high T cells potentially contribute to T cell homeostasis control

Results

Discussion

Materials and Methods