CD28 individual signals amplify pro-inflammatory cytokine production in relapse-remitting multiple sclerosis T lymphocytes.

CD28 may be considered one of the most important costimulatory receptor that by binding its cognate ligands B7.1/CD80 or B7.2/CD86 on the surface of professional antigen presenting cells (APCs), lowers TCR activation threshold and leads to the augmentation of early signalling events necessary for efficient cytokine production, cell cycle progression and survival. The role of CD28 in multiple sclerosis (MS) has been often evaluated as the source of costimulatory signals integrating those delivered by TCR and blockade of CD28/B7 interaction by recombinant CTLA4-Ig, which binds B7 molecules with high affinity, is being evaluated for the use in MS patients. However, CD28 is also able to act as a unique signalling receptor and to arise TCR-independent autonomous signals. We have previously demonstrated that CD28 stimulation by agonistic antibodies or B7 expressed on APCs, in the absence of TCR engagement, is able to activate a specific NF-κB pathway in peripheral CD4+ T cells, leading to both the production of pro-inflammatory cytokine/chemokines and to the activation of survival genes.. NF-κB has been defined as a central mediator of the immune responses, by regulating the expression of over 150 genes including chemokines, cytokines and adhesion molecules involved in inflammation. Thus, CD28 stimulation may provide TCR-independent signals, which sustain the inflammatory response in MS. By comparing the cytokine and chemokine patterns of peripheral blood CD4+ T cells isolated from relapsing-remitting MS (RRMS) patients and healthy donors (HD), we found that in RRMS but not in HD, CD28 stimulation selectively induces the expression of IL-6, IL-21 and IL-17A, all cytokines related to the Th17 cell profile phenotype. We also demonstrate that the up-regulation of all pro-inflammatory cytokines tested was dependent on CD28-mediated phosphatydilinositol 3 kinase (PI3K) activation. Therefore,CD28 could be considered as a novel receptor molecule that may contribute to amplify the inflammatory response in RRMS by favouring pro-inflammatory cytokine production and Th17 amplification.