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

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.

CD4+LAG-3+ T cells are decreased in active psoriatic arthritis patients and their restorationin vitrois mediated by TNF inhibitors

“…We have previously shown that anti-TNF reduced the activated CD4 + CD25 + T cells derived from PBMCs of PsA patients in vitro [35]. These findings were consolidated with recently published reports demonstrating that LAG-3 inhibited CD4 + T cell activation [36] and that LAG-3 was up-regulated in the reduced activated cells [37]. The mechanisms proposed for anti-TNF ability to increase T regs function are through FoxP3 mRNA and protein up-regulation and restoration of suppressive function through TNF receptor 2 on T regs [38].…”

Pathogenesis and Function of Interleukin-35 in Rheumatoid Arthritis

“…Evidence shows a decreasing arthritis index, and promoting apoptosis in CIA mice, which is injected with IL-35 intraperitoneally ( Li et al, 2016b ). Moreover, by upregulating the secretion of IL-35, it is found that IL-35 reduces antigen-specific local inflammation and impaired disease development of RA in CIA mice ( Yin et al, 2016 ; Koga et al, 2021 ). Besides, the antagonist of IL-35 is injected into the joint space and exerted the highest anti-inflammatory effects ( Abdi et al, 2018 ).…”

Balancing the Nanoscale Organization in Multivalent Materials for Functional Inhibition of the Programmed Death-1 Immune Checkpoint

“…We included WT DCs and IL-10-secreting DCs (IL-10 DCs) as immunogenic and tolerogenic DC models, respectively (Figure a). The tolerogenic features of IL-10 DCs were previously characterized by significant downregulation of stimulatory surface markers such as MHC-II, CD40, CD80, and CD86 compared to WT DCs upon stimulation . Additionally, we used the B16 melanoma line (B16) as a tumor cell model that expresses PD-L1 to investigate how the blocking efficacy compares to DCs, as tumor cells are known to inhibit immune activation (Figure a).…”