Tissue-resident CD8+ memory T cell and fibroblast cross-talk in juvenile idiopathic arthritis

Background:
Juvenile idiopathic arthritis is one of the most common autoimmune conditions of childhood, occurring when the immune system mistakenly attacks joints, leading to inflammation and pain. Around 10,000 children in the UK suffer from this debilitating condition. Currently, the majority of patients have ongoing disease even after a decade of treatment. Therefore, more research is needed into how the disease can be cured, rather than just controlled.

When the immune system mounts an attack against something, some immune cell types remain behind; keeping a memory of the target it was trying to destroy ('memory cells'). Memory cells ensure the immune system can mount a rapid and effective attack if the target is found again in the body. With arthritis in mice, a specific type of memory cell has been found in the joint, which has the ability to activate inflammation again after the arthritis has resolved. In children with juvenile idiopathic arthritis, cells that resemble this type of memory cell have been found in much higher levels in fluid taken from the joints compared to the blood stream, suggesting they are accumulating where the disease is occurring. In other parts of the body, other cell types anchor memory cells to ensure they remain at sites where they are needed and provide signals to ensure memory cells survive for a long time. It is not clear at present which cells might be doing this in the joint and what role memory cells have in juvenile idiopathic arthritis.

Aims and Objectives:
I aim to test the question of whether repeat flares of inflammation keep occurring in children with juvenile idiopathic arthritis because these memory cells remain in the joint, resisting treatment. In particular I will investigate whether cells known as fibroblasts, which contribute to the connective tissue of the joint, interact with these memory cells to help them to survive and persist in the joint. The plan is to characterise these cells in the joints of children with arthritis, identifying signalling pathways and processes used by the cells. Advances in technology mean that it is now possible to look at the level of individuals cells to see which proteins these cells are making, providing minute resolution of the cell activities. I will investigate how these cells differ in children who get very severe disease. Finally, in genetically-modified mice with arthritis it is possible to eliminate types of fibroblast cells; I will investigate how this impacts the memory cells in joints.

Potential Applications and Benefits:
The processes that initiate inflammation may not be the same as those perpetuating it, as the disease process evolves. Understanding the cells and processes causing ongoing inflammation in arthritic joints will likely be key for finally achieving a cure for children and adults with autoimmune arthritis. Currently these memory cells are not directly targeted by any available treatments. If memory cells are contributing to ongoing inflammation, we need to know which signals they are responding to in the joint to target them effectively. Treatments affecting the fibroblasts are under development for adults, but further understanding of fibroblasts in childhood arthritis is needed to determine whether these therapies are also likely to be effective in children.

Fluid from the joint is easier to obtain than joint tissue, but the downside is that it captures immune cells much better than connective tissue cells, like fibroblasts. Since we will collect and analyse the tissue and the fluid from the same joints, we will learn how the cells in the fluid reflect the biology in the joint tissue. This understanding provides a starting point for developing new therapies that target fibroblasts and novel tests that improve our selection of treatment.

The majority of children with juvenile idiopathic arthritis (JIA) do not achieve remission despite years of treatment, resulting in joint damage and long-term disability. In murine models, a long-lived tissue-resident CD8+ memory T cell (TRM) population has been identified that resides in the joint during remission and mediates inflammatory flares. Clonally-expanded TRM-like cells are enriched in the synovial fluid of patients with JIA. In other contexts, fibroblast subsets have been shown to produce maintenance factors, metabolically re-programme and enhance CD8+ T cell survival. Therefore, I aim to explore whether persistence of inflammation in JIA is driven by cross-talk between fibroblast subsets and TRM, enhancing TRM retention, survival and longevity.

My objectives include functionally characterising TRM and fibroblast subsets of the inflamed tissue from patients with JIA at diagnosis; determining how differences in these populations relate to disease trajectory and assessing the functional importance of interactions between these subsets in the inflamed joint.

I will analyse synovial biopsies and synovial fluid from children with JIA using multi-omics platforms and immunofluorescence imaging, characterising the transcriptomic and proteomic profiles of cellular subsets at a single cell level of resolution. Independent datasets of bulk-RNA sequenced synovial fluid will be used to verify findings. Murine models of antigen-induced arthritis in transgenic mice will enable investigation of selective depletion or transfer of the cellular subsets.

TRM are not currently directly targeted by any of the available treatments. Fibroblast-targeting therapies are under development for arthritis in adults, but further characterisation of fibroblasts in JIA is needed to determine the likely efficacy in children. Understanding the mechanisms mediating persistence of inflammation in joints is critical for achieving sustained clinical remission and cure of arthritis