Tissue-adaptive effector cells promote tissue damage in SLE
Lupus nephritis – inflammation of the kidney caused by systemic lupus erythematosus – is a common complication that can profoundly affect the quality of life and lifespan of lupus patients. It is known that T cells, a type of immune cell, enter the kidneys of lupus patients where they are thought to contribute to organ damage. However, the factors that transform the T cells leading them to enter the kidneys are not well defined. Moreover, whether the entry of these T cells causes organ damage in lupus nephritis is yet to be established.
Dr. Craft will use the Distinguished Innovator Award to study T cell populations that were recently found in the kidneys of lupus nephritis patients. Using mouse lupus models in parallel with kidney tissue samples from lupus patients, the research team will determine how T cells undergo changes to become destructive in the kidneys and whether their presence in the kidney causes tissue damage.
What this study means for people with lupus
Clear understanding of T cell populations found in the kidneys of lupus nephritis patients will inform how organ damage occurs and that will open the door for new therapeutic targets and interventions.
Tissue injury is a major cause of morbidity and mortality in SLE. Yet, there is limited knowledge of the mechanistic pathways that cause organ damage in lupus. This lack of insight hampers targeted use of current therapeutics and application of those in development. We have identified a cytotoxic T cell effector program associated with tissue damage in human and murine lupus nephritis. We also have found a stem-like progenitor T cell population with self-renewal capacity, resident in renal lymph nodes, gives rise to the cytotoxic effector cells in lupus nephritis, with the latter having the capacity to cause kidney injury. This program of T cell differentiation, from stem-like progenitors in lymphoid organs to tissue effector cells, is analogous to that observed in humans and mice with chronic infection and with cancer, respectively, states of continual antigen presentation as in SLE. By contrast to infection and cancer, however, in which activation of cytotoxic cells is necessary for elimination of virally infected and tumor cells, we believe this differentiation program sustains tissue damage in lupus. Our data, and by analogy, data from humans and mice with chronic infection and cancer, lead to our hypothesis, one to our knowledge has not been proposed in SLE: Canonical immune effector programs conserved across vertebrate evolution that are operative upon organismal insult, for example in infection or upon cellular transformation, also drive tissue injury in lupus. These programs proceed along an epigenetically regulated pathway, from stem-like progenitors in resident lymphoid organs to effector cells in tissue, which in the case of lupus leads to organ injury. The advantage of using this strategy, analogizing well-described immune effector programs described in other conditions to those we anticipate occur in SLE, is application of phenotypic and mechanistic insights gleaned from study of different disease states to enable understanding of tissue damage in lupus. We can thus utilize information from our knowledge of how the immune system functions canonically, in this case in non-autoimmune diseases of chronic immune activation including cancer and infection (conditions we investigate in the lab and thus have considerable knowledge) to predict pathways that incite tissue damage in SLE. If so, we can use the aggregated information to identify new targets for therapeutic manipulation, or better personalize existing therapies or those in development. Our aims are to first characterize the gene regulatory and transcriptional network driving the cytotoxic T cell program in lupus nephritis, and second, determine if T cell cytotoxicity effects tissue damage, and if so, how. We will use murine lupus models in parallel with experiments using tissue samples from SLE patients. Mouse models are tools for mechanistic study, with their utility magnified when investigated alongside patients.