Role of Dendritic Cell Subsets in Immunity and Their Contribution to Non-infectious Uveitis

Dendritic cells (DCs) are a heterogeneous population. Murine DCs consist of conventional DCs (cDCs) and plasmacytoid DCs (pDCs). In human, the analogous populations are myeloid DCs (mDCs) and pDCs. Though distinct in phenotypes and functions, studies have shown that these DC subsets may interact or ‘crosstalk’ during immune responses. For example, cDCs may facilitate pDC maturation, while pDCs may enhance antigen presentation of cDCs in certain pathogenic conditions or even take on a cDC phenotype themselves. The role of DCs in non-infectious uveitis has been studied primarily in the experimental autoimmune uveitis mouse model and to a more limited extent in patients. Recent evidence shows that the number, phenotype and function of DC subsets are altered in this disease. We provide an overview of selected recent developments of pDCs and cDCs/mDCs, with special attention to their interaction and the dual roles of DC subsets in non-infectious uveitis

Increased CD1c+ mDC1 with mature phenotype regulated by TNFα-p38 MAPK in autoimmune ocular inflammatory disease

In this study we investigated the role of blood CD1c(+) myeloid dendritic cells 1 (mDC1), a key mDC subtype, in patients with autoimmune uveitis. We observed a significant increase of blood CD1c(+) mDC1 in uveitis patients. The increased CD1c(+) mDC1 exhibited high HLADR expression and less antigen uptake. CD1c(+) mDC1 were divided into two subpopulations. CD1c(hi) mDC1 subpopulation showed less antigen uptake and higher HLADR expression compared to CD1c(lo) mDC1 subpopulation. Importantly, the CD1c(hi) mDC1 subpopulation was increased in uveitis patients. In vitro, mature monocyte-derived dendritic cells (MoDCs), characterized by lower levels of antigen uptake, induced more CD62L(−)CD4(+) T helper cell proliferation. The mature phenotype and function of CD1c(+) mDC1 were regulated by TNFα via a p38 MAPK-dependent pathway. These data show that alterations in the systemic immune response are involved in the pathogenesis of autoimmune uveitis and invite the therapeutic possibility of attenuating uveitis by manipulating blood CD1c(+) mDC1

CD14++CD16+ Monocytes Are Enriched by Glucocorticoid Treatment and Are Functionally Attenuated in Driving Effector T Cell Responses

Human peripheral monocytes have been categorized into three subsets based on differential expression levels of CD14 and CD16. However, the factors that influence the distribution of monocyte subsets and the roles which each subset plays in autoimmunity are not well studied. Here we show that circulating monocytes from patients with autoimmune uveitis exhibit a skewed phenotype towards intermediate CD14(++)CD16(+) cells, and that this is associated with glucocorticoid therapy. We further demonstrate that CD14(++)CD16(+) monocytes from patients and healthy control donors share a similar cell surface marker and gene expression profile. Comparison of the effects of intermediate CD14(++)CD16(+) monocytes with classical CD14(++)CD16(−) and non-classical CD14(+)CD16(++) monocytes revealed that the intermediate CD14(++)CD16(+) subset had an attenuated capacity to promote both naïve CD4(+) T cell proliferation and polarization into a Th1 phenotype, and memory CD4(+) T cell proliferation and IL-17 expression. Furthermore, CD14(++)CD16(+) cells inhibit CD4(+) T cell proliferation induced by other monocyte subsets and enhance CD4(+) T regulatory cell IL-10 expression. These data demonstrate the impact of glucocorticoids on monocyte phenotype in the context of autoimmune disease and the differential effects of monocyte subsets on effector T cell responses

Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A

Glucocorticoids remain the cornerstone of treatment for inflammatory conditions, but their utility is limited by a plethora of side effects. One of the key goals of immunotherapy across medical disciplines is to minimize patients' glucocorticoid use. Increasing evidence suggests that variations in the adaptive immune response play a critical role in defining the dose of glucocorticoids required to control an individual's disease, and Th17 cells are strong candidate drivers for nonresponsiveness [also called steroid resistance (SR)]. Here we use gene-expression profiling to further characterize the SR phenotype in T cells and show that Th17 cells generated from both SR and steroid-sensitive individuals exhibit restricted genome-wide responses to glucocorticoids in vitro, and that this is independent of glucocorticoid receptor translocation or isoform expression. In addition, we demonstrate, both in transgenic murine T cells in vitro and in an in vivo murine model of autoimmunity, that Th17 cells are reciprocally sensitive to suppression with the calcineurin inhibitor, cyclosporine A. This result was replicated in human Th17 cells in vitro, which were found to have a conversely large genome-wide shift in response to cyclosporine A. These observations suggest that the clinical efficacy of cyclosporine A in the treatment of SR diseases may be because of its selective attenuation of Th17 cells, and also that novel therapeutics, which target either Th17 cells themselves or the effector memory T-helper cell population from which they are derived, would be strong candidates for drug development in the context of SR inflammation