Targeting peripheral T cell-B cell interactions in SLE
Which helper T cells spur B cell cells to produce harmful antibodies in lupus is unclear. Recently, we discovered a new cell variety, the T peripheral helper (Tph) cell, that activates B cell responses and antibody production in patients with rheumatoid arthritis. These cells are also common in the blood of patients with lupus, and our study will ask whether they are important in the disease. Our project will determine how abundant the cells are in patients who have recently been diagnosed with the disease and how current immune-suppressing medications alter their numbers. We are also examining the types of B cell responses that Tph cells stimulate, as well as the chemical messages that promote formation of Tph cells and keep them functioning. In particular, we will ask whether a T cell protein known as the aryl hydrocarbon receptor helps activate Tph cells. These studies may identify new ways to interfere with the cells, such as by targeting the aryl hydrocarbon receptor, that could inhibit destructive immune responses and thus treat lupus.
What this study means for people with lupus
“In lupus, B cells can produce antibodies that damage patients’ own tissues—but only if the cells first interact with another type of immune cell called a helper T cell. We have discovered a new type of helper T cell that may provide the stimulation B cells need to start making self-destructive antibodies. The insights our work provide may allow development of new treatments for lupus that target these T cells.”
Interrupting that pathologic autoimmune response in lupus remains a central challenge in treating this disease. Disease activity in lupus characteristically involves rising titers of autoantibodies and expansion of plasmablasts, suggesting ongoing T cell-B cell interactions and B cell activation. T follicular helper (Tfh) cells are generally considered the principal T cell population capable of helping B cells; however, the T cell populations most important in driving the pathologic B cell response in lupus remain unclear. Using high-dimensional approaches, we recently discovered a new T cell subset, named ‘T peripheral helper (Tph) cells,’ that is markedly expanded in the joints of patients with rheumatoid arthritis (Rao et al, Nature, 2017). Tph cells display a unique capacity to infiltrate inflamed tissues and drive B cell responses within tissues. Preliminary data now show that Tph cells are dramatically expanded in the circulation of patients with lupus nephritis and correlate with dsDNA titers and plasmablast frequencies. The discovery of Tph cells has immediate clinical implications for lupus. It is critical to understand that effects of current therapies in use – and new methods being developed to target Tfh cells – on the Tph cell population. Further, given the dramatic expansion of Tph cells in autoimmune diseases, we hypothesize that selective targeting of Tph cells could blunt the pathologic immune response without causing global immunosuppression. The overall objective of this proposal is to understand the potential roles of Tph cells in lupus, including their expansion in early SLE, their capacity to induce relevant B cell responses, and the regulation of their function.
The specific aims utilize three complementary approaches to evaluate the role of Tph cells in lupus. Aim 1 will evaluate the functions of Tph cells in inducing specific B cell phenotypes and effector functions relevant in lupus, with comparison to Tfh cells. Aim 2 will examine signals that control the differentiation and function of Tph cells, with a particular focus on one novel, targetable regulator. Aim 3 will measure the expansion of Tph cells in patients with early SLE and the effects of current SLE treatment on Tph cells.
Through a combination of mechanistic studies and cutting-edge technologies using human samples, coupled with analyses of SLE patients, this study will provide critical insights into the roles of Tph cells in the autoimmune pathology of lupus. Understanding these aspects of Tph cells, in the context of established work on Tfh cells, is essential for predicting the effects of therapies that influence T cell-B cell interactions on lupus pathology, and may highlight a unique role for Tph cells that can be specifically targeted to treat lupus.