CD26-Mediated Induction of EGR2 and IL-10 as Potential Regulatory Mechanism for CD26 Costimulatory Pathway

Abstract

CD26 is associated with T cell signal transduction processes as a costimulatory molecule, and CD26+ T cells have been suggested to be involved in the pathophysiology of diverse autoimmune diseases. Although the cellular and molecular mechanisms involved in CD26-mediated T cell activation have been extensively evaluated by our group and others, potential negative feedback mechanisms to regulate CD26-mediated activation still remain to be elucidated. In the present study, we examine the expression of inhibitory molecules induced via CD26-mediated costimulation. We show that coengagement of CD3 and CD26 induces preferential production of IL-10 in human CD4+ T cells, mediated through NFAT and Raf-MEK-ERK pathways. A high level of early growth response 2 (EGR2) is also induced following CD26 costimulation, possibly via NFAT and AP-1–mediated signaling, and knockdown of EGR2 leads to decreased IL-10 production. Furthermore, CD3/CD26-stimulated CD4+ T cells clearly suppress proliferative activity and effector cytokine production of bystander T cells in an IL-10–dependent manner. Taken together, our data suggest that robust CD26 costimulatory signaling induces preferential expression of EGR2 and IL-10 as a potential mechanism for regulating CD26-mediated activation.

First-in-human phase 1 of YS110, a monoclonal antibody directed against CD26 in advanced CD26-expressing cancers

“…In view of these recent findings, data from our current trial showing that serum DPPIV activity was decreased following treatment with YS110 in a dose-dependent manner (Figure 2B). It would suggest that anti-tumour activity via DPPIV inhibition may constitute yet another mechanism of action for the anti-tumour activity of YS110, in addition to the mechanisms of action discussed above (Hatano et al , 2015). …”

Dipeptidyl peptidase 4 inhibitors and their potential immune modulatory functions

“…Interestingly, CD26-mediated co-stimulation of CD8(+) T cells results in greater cytotoxic effect than that induced by CD28 co-stimulation pathway (Hatano et al, 2013). The modulation of CD26 on CD8(+) T lymphocytes may use costimulatory transduction mediated by early growth response 2 (EGR2) and IL-10 (Hatano et al, 2015;Pinheiro et al, 2017).…”

Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins

“…DPP4/ CD26 is involved in T cell activation, T cell signalling and T cell differentiation due to its interactions with ADA, CD45, caveolin-1, CARMA-1 and M6P/IGFII-R [9]. These processes are regulated by the cytokines IL-2, IL-6, IL-10, IL-12, IL-17, IL-29, IFN-g and TGF-b, as well as compartmentation of DPP4/CD26 to either lipid rafts or internalization [8,9,48,88,89,[91][92][93]. Furthermore, post-translation modification of DPP4/CD26 such as sialylation also appears to influence compartmentation and/or the interactions with its binding partners [9,86,87,90].…”

“…However, comparing CD28 versus CD26 co-stimulation of CD3 mediated T cell activation, CD26 co-stimulation was found to induce production of IL-10 preferentially in human CD4 1 T cells mediated via nuclear factor of activated T cells (NFAT) and rapidly accelerated fibrosarcomamitogen-activated protein kinase-extracellular signalregulated kinase (Raf-MEK-ERK) pathways, as well as high levels of early growth response 2 (EGR2) mediated possibly via NFAT and activator protein 1 (AP-1)-signalling. Furthermore, CD26-mediated co-stimulation of CD4 1 T cells induced greater lymphocyte-activation gene 3 (LAG3) expression than CD28-mediated co-stimulation [92]. Whether or not the other DASH proteins contribute to the overall DPP4-like activity in Th2 cells such DPP8 still needs to be investigated [2,7,13,51,88,94,95].…”