CD4+ T cells regulate the formation and function of inflammatory dendritic cells [electronic resource]

Monocytes rapidly infiltrate inflamed tissues and differentiate into inflammatory dendritic cells (DCs) that mediate pathogen clearance. However, the cellular and molecular mechanisms governing inflammatory DC formation and subsequent function remain elusive. Current evidence suggests that conserved molecular patterns present on different classes of microbes that engage pattern recognition receptors on DCs dictate the type of immune response initiated by DCs. Given that pathogens are under evolutionary pressure to avoid elimination, we reasoned that memory T cells were better positioned to inform the immune response. The studies presented in this dissertation indicate that memory T cells dictate the nature of the immune response through the induction of functionally specialized inflammatory DCs. Our studies indicate that T-helper (TH) cells interact with monocytes in inflamed tissues and instruct monocytes to differentiate into inflammatory DCs in vivo. This process is antigen-driven and requires cell contact, GM-CSF and TNF[alpha]. Interestingly, distinct TH cell subsets direct the formation of specialized DC subsets. In psoriasis lesions, TH1 and TH17 cells interact with monocytes and instruct these cells to differentiate into TH1- and TH17-promoting DCs, respectively. Correspondingly, in acute atopic dermatitis, TH2 cells interact with monocytes and elicit the formation of TH2-promoting DCs. Again, DC formation required GM-CSF and cell contact, whereas TH subset specific cytokines dictate DC function and the expression of DC subset specific surface molecules. Moreover, the phenotypes of T cell induced DC subsets are maintained following subsequent stimulation with a panel of toll-like receptor (TLR) agonists, suggesting that TH-derived signals outweigh downstream TLR signals in their influence on DC function. Our preliminary studies indicate that regulatory T cells promote the formation of tolerogenic DCs that are typically associated with tumor progression and poor patient prognosis. The data indicate that intra-tumoral Tregs frequently interact with monocytes within tumor tissue and instruct monocytes to differentiate into IL-10-producing tolerogenic DCs. Such Treg-induced DCs (DCTreg) are subsequently able to instruct naïve T cells to differentiate into FoxP3+, IL-10-producing regulatory T cells with potent suppressive activity. The capacity of Tregs to elicit DCTreg formation represents a physiologic mechanism that on one hand amplifies and perpetuates immune tolerance, but also contributes to attenuated anti-tumor immune responses. We also explored mechanisms capable of depleting inflammatory DCs. While previous studies have indicated that inflammatory DC depletion through systemic elimination of their monocyte precursors with clodronate-loaded liposomes ameliorates pathogenesis in psoriasis and other diseases, translation of these strategies into the clinic is difficult due the importance of monocytes in the clearance of infection. We describe three strategies that avoid the monocyte intermediates in order to directly prevent inflammatory DC formation or deplete inflammatory DCs through antibody-loaded toxins. These strategies provide useful tools for the targeted reduction of inflammatory DCs during disease pathogenesis. In summary, memory T cells dictate the nature of the immune response through the induction of functionally specialized inflammatory DCs. The system we utilized for generating DC subsets with differential TH polarizing capacity has facilitated the elucidation of cell surface and soluble factors governing the biology of TH-promoting DC subsets. These and additional molecules expressed by DC subsets should prove useful for detecting and quantifying each subset in situ and may enable the design of novel therapeutic strategies for T[not]H-associated inflammatory diseases.

Advisor: Engleman Edgar G. primary advisor. Thesis advisor
Lee Peter advisor. Thesis advisor
Negrin Robert S. advisor. Thesis advisor
Utz Paul advisor. Thesis advisor