T-Cell Costimulatory Pathways and Their Influence in Inflammatory Disease

Costimulatory molecules can promote or inhibit T cell receptor mediated activation playing an important role in fine-tuning TCR-mediated T cell activation. T cell function is ultimately dictated by an array of costimulatory signals and it has become clear that the relative importance of a costimulatory pathway may vary depending on the T cell subset and the specific mechanism of pathogenesis. 

Given that the alternative costimulatory pathway comprised of CD226 and its ligand CD155 has been associated with autoimmune diseases, including multiple sclerosis (MS) and type 1 diabetes (T1D), we investigated the functional role of CD226 and the effects of specifically targeting CD226 on human T cell responses. Furthermore, CD155 binds with higher affinity to TIGIT, a co-inhibitory receptor that can transduce a negative signal into activated T cells that attenuates T cell proliferation and cytokine production. In fact ligation of TIGIT by agonistic antibody inhibits IL-2 production and T cell activation. In summary, targeting this costimulatory pathway may provide a therapeutic approach that specifically modulates the pro-inflammatory (Th1/Th17)/ anti-inflammatory (Th2) balance in a wide range of inflammatory diseases.

Bio Profile

Liliana Lucca, PhD

Associate Research Scientist

View Full Profile

Podoplanin as a New Contributory Marker to Establishment of Autoimmunity

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system in which the myelin sheaths surrounding the axons in the brain and spinal cord are damaged by a chronic autoimmune process. Some patients have structures resembling lymph nodes in the meninges surrounding the brain, which are known as ectopic lymphoid follicles. These meningeal follicles are topographically associated with disease lesions in the grey matter cortex, and patients who have worse meningeal inflammation progress to disability more quickly. In a mouse model for MS, a molecule called podoplanin (PDPN) has been shown to be necessary for ectopic lymphoid follicle formation in the meninges. Additionally, in this mouse model, PDPN has been demonstrated to be specifically present on Th17 cells, a subset of immune cells known to be important to MS pathogenesis.

 We hypothesize that PDPN is a marker of highly activated pathogenic cells in humans and that PDPN contributes to the formation of ectopic lymphoid follicles in MS patients. 

This project will explore an important unanswered question in MS research about the role of PDPN in the formation of meningeal ectopic lymphoid follicles, reveal new mechanisms of the immunopathology that may contribute to progressive neurological impairment in MS, and potentially open the door to a new therapeutic target in MS therapy.