Ricerc@Sapienza

Introduction CD28 is an important costimulatory receptor for T lymphocytes that, in humans, may delivers TCR-independent signal leading to the up-regulation of pro-inflammatory cytokines. We have recently reported that CD28 autonomous signalling induces the expression of IL-17A in peripheral CD4+ T lymphocytes from healthy donors, Multiple Sclerosis and type 1 diabetes patients.

CD28 is an important co-stimulatory receptor for T lymphocytes that, in humans, delivers TCR-independent signal leading to the up-regulation of pro-inflammatory cytokines. We have recently reported that CD28 autonomous signaling induces the expression of IL-17A in peripheral CD4+ T lymphocytes from healthy donors, multiple sclerosis, and type 1 diabetes patients. Due to the relevance of IL-17A in the pathophysiology of several inflammatory and autoimmune diseases, we characterized the mechanisms and signaling mediators responsible for CD28-induced IL-17A expression.

Phosphatidylinositol 4,5-biphosphate (PIP2) is a membrane phospholipid that controls the activity of several proteins regulating cytoskeleton reorganization, cytokine gene expression, T cell survival, proliferation, and differentiation. Phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) are the main enzymes involved in PIP2 biosynthesis by phosphorylating phosphatidylinositol 4-monophosphate (PI4P) at the D5 position of the inositol ring. In human T lymphocytes, we recently found that CD28 costimulatory molecule is pivotal for PIP2 turnover by recruiting and activating PIP5Ka.

CD28 superagonistic antibodies (CD28SAb) can preferentially activate and expand immunosuppressive
regulatory T cells (Treg) in mice. However, pre-clinical trials assessing
CD28SAbs for the therapy of autoimmune diseases reveal severe systemic inflammatory
response syndrome in humans, thereby implying the existence of distinct signalling abilities
between human and mouse CD28. Here, we show that a single amino acid variant within the
C-terminal proline-rich motif of human and mouse CD28 (P212 in human vs. A210 in mouse)