Abstract
The small molecule cyclotriazadisulfonamide (CADA) down-modulates the human CD4 receptor, an important factor in T cell activation. Here, we addressed the immunosuppressive potential of CADA using different activation models. CADA inhibited lymphocyte proliferation with low cellular toxicity in a mixed lymphocyte reaction, and when human PBMCs were stimulated with CD3/CD28 beads, phytohemagglutinin or anti-CD3 antibodies. The immunosuppressive effect of CADA involved both CD4+ and CD8+ T cells but was, surprisingly, most prominent in the CD8+ T cell subpopulation where it inhibited cell-mediated lympholysis. Immunosuppression by CADA was characterized by suppressed secretion of various cytokines, and reduced CD25, phosphoSTAT5 and CTPS-1 levels. We discovered a direct down-modulatory effect of CADA on 4-1BB (CD137) expression, a survival factor for activated CD8+ T cells. More specifically, CADA blocked 4‑1BB protein biosynthesis by inhibition of its co-translational translocation into the ER in a signal peptide-dependent way. Taken together, this study demonstrates that CADA, as potent down-modulator of human CD4 and 4‑1BB receptor, has promising immunomodulatory characteristics. This would open up new avenues toward chemotherapeutics that act as selective protein down-modulators to treat various human immunological disorders.
Highlights
The cluster of differentiation 4 (CD4) receptor is a type I integral membrane protein consisting of four extracellular immunoglobulin-like domains, a spanning transmembrane region and a short cytoplasmic tail [1]
Based on this human CD4 (hCD4) receptor down-modulating potency of CADA, we addressed whether CADA has a potential immunomodulatory capacity in human cells
Whereas Jurkat T cells barely responded to staphylococcal enterotoxin B (SEB), they were highly activated by the superantigen staphylococcal enterotoxin E (SEE), as evidenced by the profound CD69 expression (Supplementary Figure 1A)
Summary
The cluster of differentiation 4 (CD4) receptor is a type I integral membrane protein consisting of four extracellular immunoglobulin-like domains, a spanning transmembrane region and a short cytoplasmic tail [1]. Several immune cell types express the CD4 receptor with T helper cells expressing the highest levels, followed by monocytes that express already 10- to 20-fold less CD4 compared to T cells [4]. The CD4 receptor is crucial for proper immune function, especially during T cell activation in which it can fulfil several roles [6]. More important are the signaling function of the CD4 receptor in T cell activation through Lck and the enhancement of T cell sensitivity to antigens mediated by CD4 [8, 9]. Besides its role in T cell activation, the CD4 receptor is suggested to be involved in peripheral T cell differentiation towards the T helper 2 subset and in the chemotactic response of CD4+ T cells towards interleukin (IL)-16 [10, 11]. The important role of the CD4 receptor in the immune system has been further demonstrated by the in vitro and in vivo immunosuppressive potential of non‐depleting anti-CD4 monoclonal antibodies [14,15,16]
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