IL10- and IL35-Secreting MutuDC Lines Act in Cooperation to Inhibit Memory T Cell Activation Through LAG-3 Expression.

Marianna M Koga,Adrien Engel,Mathias Stevanin,Christine Lavanchy,Bernard L Schneider,Matteo Pigni,Hans Acha-Orbea,Vanessa Laversenne

doi:10.3389/fimmu.2021.607315

Abstract

Dendritic cells (DCs) are professional antigen-presenting cells involved in the initiation of immune responses. We generated a tolerogenic DC (tolDC) line that constitutively secretes interleukin-10 (IL10-DCs), expressed lower levels of co-stimulatory and MHCII molecules upon stimulation, and induced antigen-specific proliferation of T cells. Vaccination with IL10-DCs combined with another tolDC line that secretes IL-35, reduced antigen-specific local inflammation in a delayed-type hypersensitivity assay independently on regulatory T cell differentiation. In an autoimmune model of rheumatoid arthritis, vaccination with the combined tolDCs after the onset of the disease impaired disease development and promoted recovery of mice. After stable memory was established, the tolDCs promoted CD4 downregulation and induced lymphocyte activation gene 3 (LAG-3) expression in reactivated memory T cells, reducing T cell activation. Taken together, our findings indicate the benefits of combining anti-inflammatory cytokines in an antigen-specific context to treat excessive inflammation when memory is already established.

Highlights

Dendritic cells (DC) are widely recognized as inducers of adaptive immune responses, modulating the balance between tolerance and immunity
In order to test if they kept the murine tumor DC1 (MutuDC1) phenotype, we used a panel of surface markers to distinguish DC subsets in IL10-Secreting Mutu DC Line (IL10-DC) and compared them to untransduced and mock-transduced MutuDCs
Contrary to untransduced DCs, the same augmented amount of IL-10 was detected in IL10-DCs cultured in the absence of the stimuli, suggesting that the cells were already producing the cytokine at maximum rate (Figure 1B)

Summary

Introduction

Dendritic cells (DC) are widely recognized as inducers of adaptive immune responses, modulating the balance between tolerance and immunity. To do so, they rely on the ability to sense the environment upon antigen uptake, migrate, and translate the signals met, through upregulation of MHC and co-stimulatory molecules, and secreting cytokines and inflammatory mediators. Tolerogenic DCs (tolDCs) are essential for the maintenance of central and peripheral tolerance They are able to induce clonal T cell deletion, T cell anergy, and regulatory T cell differentiation. DCs can further restrain memory and effector T cell responses due to impaired or sustained antigen presentation, insufficient co-stimulation, and tolDCs Induce LAG-3 Expression secretion of large amounts of anti-inflammatory mediators [2,3,4,5]. The stability of tolDCs and the difficulty in achieving a definitive and efficient induction protocol are issues that still need to be addressed

Methods

Results

Conclusion