On the role of co-inhibitory molecules in dendritic cell: T helper cell coculture assays aimed to detect chemical-induced contact allergy.
T cells play a pivotal role in sensitization and elicitation of type IV allergic reactions. While T helper cells sustain and maintain the differentiation of further effector cells, regulatory T cells are involved in control of cytokine release and proliferation, and T killer cells execute cellular lysis, thereby leading to certain levels of tissue damage. According to their central role, the widely applied and OECD-supported test method for the assessment of the sensitization potential of a chemical, i.e., the local lymph node assay (LLNA), relies on the detection of the immune-responsive proliferation of lymphocytes. However, most sensitization assays recently developed take advantage of the initiators of sensitization, dendritic cells (DCs) or DC-like cell lines. Here, we focus on inhibitory molecules expressed on the surface of DCs and their corresponding receptors on T cells. We summarize insight into the function of CTLA-4, the ligands of inducible co-stimulators (ICOSs), and on the inhibitory receptor programmed death (PD). The targeting of immune cell surface receptors by inhibitory molecules holds some promise with regard to the development of T cell-based sensitization assays. Firstly, a broader and more sensitive dynamic range of detection could be achieved by blocking inhibitors or by removing inhibiting regulatory T cells from the assays. Secondly, the actual expression levels of inhibitory molecules could be also a valuable indicator for the process of sensitization. Finally, inhibitory molecules in coculture test systems are supposed to have a major influence on DCs by reverse signaling, thereby affecting their differentiation and maturation status in a feedback loop. In conclusion, inhibitory ligands of DC surface receptors and/or their cognate receptors on T cells could serve as useful tools in cell-based assays, directly influencing toxicological endpoints such as sensitization.
Department of Product Safety, German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, 10589, Berlin, Germany, Matthias.Peiser@bfr.bund.de.
Matthias
M
Peiser
Manuel
M
Hitzler
Andreas
A
Luch
D000485:Allergens / Q000276:immunology* / Q000633:toxicity; D000818:Animals; D018920:Coculture Techniques; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000276:immunology / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D003877:Dermatitis, Contact / Q000209:etiology / Q000276:immunology*; D006241:Haptens / Q000276:immunology* / Q000633:toxicity; D006801:Humans; D007158:Immunologic Techniques; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism
D000485:Allergens; D061025:Costimulatory and Inhibitory T-Cell Receptors; D006241:Haptens; D011948:Receptors, Antigen, T-Cell