Recombinant Human CD40 Protein (a.a. 108-261) [His]

There is accumulating evidence that patients with primary Sjogren's syndrome (pSS) display aberrant CD4+ T cell responses, both in the peripheral compartment and in the inflamed salivary glands. CD4(+) T cell abnormalities are also critically associated with B cell hyper activation, one of the hallmarks of disease, which is linked with disease severity and evolution to lymphoma. T cell activation and the cross-talk between T and B cells are tightly regulated by the balance between costimulatory pathways, such as the interactions between CD80/CD86:CD28, CD40:CD40L and ICOS:ICOSL, and co-inhibitory signals, including the immunoregulatory CTLA-4 protein. Evidence from patients with pSS as well as data from animal models of the disease suggests that these pathways play a critical role in pSS pathogenesis and their targeting could be exploited for therapeutic purposes. In this review, we first summarise the evidence implicating aberrant T cell co-stimulation and co-inhibition in driving the disease before focusing on the results of recent randomised controlled trials (RCTs) with compounds able to block T cell co-stimulation and enhance T cell coinhibition. Despite a clear biological effect on downstream B cell activation has been observed in patients treated with CTLA-4-Ig (abatacept) and with monoclonal antibodies targeting CD40 and ICOSL, the clinical efficacy of this approach has so far yielded mixed results; while the anti-CD40 monoclonal antibody iscalimab showed significant improvement in systemic disease activity compared to placebo, two large RCTs with abatacept and a phase IIa RCT with an anti-ICOSL monoclonal antibody (prezalumab) failed to reach their primary endpoints. Although the discrepancies between biological and clinical efficacy of targeting T cell costimulation on pSS remain unresolved, several factors including drug bioavailability and receptor occupancy, patient stratification based on T-cell related biomarkers and the choice of study outcome are likely to play an important role and form the basis for further work towards the quest for a disease-modifying biologic therapy in pSS.

The glycoprotein CD83 is known to be expressed by different immune cells including activated CD4(+) Foxp3(+) regulatory T cells (Tregs) and CD4(+) Foxp3(-) conventional T cells. However, the physiological function of endogenous CD83 in CD4(+) T cell subsets is still unclear. In this study, we have generated a new CD83(flox) mouse line on BALB/c background, allowing for specific ablation of CD83 in T cells upon breeding with CD4-cre mice. Tregs from CD8(flox/flox)/CD4-cre(tg/wt) mice had similar suppressive activity as Tregs from CD83(flox/flox)/CD4-cre(wt/wt) wild-type littermates, suggesting that endogenous CD83 expression is dispensable for the inhibitory capacity of Tregs. However, CD83-deficient CD4(+) conventional T cells showed elevated proliferation and IFN-gamma secretion as well as an enhanced capacity to differentiate into Th1 cells and Th17 cells upon stimulation in vitro. T cell-specific ablation of CD83 expression resulted in aggravated contact hypersensitivity reaction accompanied by enhanced CD4(+) T cell activation. Moreover, adoptive transfer of CD4(+) CD45RB(high) T cells from CD83(flox/flox)/CD4-cre(tg/wt) mice into Rag2-deficient mice elicited more severe colitis associated with increased serum concentrations of IL-12 and elevated CD40 expression on CD11c(+) dendritic cells (DCs). Strikingly, DCs from BALB/c mice cocultured with CD83-deficient CD4(+) conventional T cells showed enhanced CD40 expression and IL-12 secretion compared with DCs cocultured with CD4(+) conventional T cells from CD83(flox/flox)/CD4-cre(wt/wt) wild-type mice. In summary, these results indicate that endogenous CD83 expression in CD4(+) conventional T cells plays a crucial role in controlling CD4(+) T cell responses, at least in part, by regulating the activity of CD11c(+) DCs.