Examining the role of T cell exhaustion in lupus pathogenesis

In people with lupus, T cells invade the kidneys and other organs and trigger damage. However, Dr. Tilstra’s team has found that some of these T cells have lost the ability to attack—researchers describe them as “exhausted.” In this project they aim to determine whether the cells wear out before or after they enter the kidneys and whether the kidneys cause this change. They will also ask whether the number of exhausted T cells in patients’ kidneys predicts how severe their lupus symptoms will be. Understanding how T cells become exhausted may enable scientists to design treatments that tire out harmful immune cells and reduce the damage to patients’ kidneys and other organs.

What this study means for patients

Immune cells called T cells injure the kidneys and other organs in patients with lupus. But some of the T cells in the organs appear to be worn out and can no longer cause problems. Dr. Tilstra’s work will figure out how these cells become “tired,” so researchers can develop new treatments to exhaust harmful immune cells while sparing the immune cells that protect against infections.

While T cells are central to the pathogenesis of systemic lupus erythematosus (SLE), little is known about how T cells function after infiltrating target organs. The current paradigm suggests that kidney infiltrating T cells (KITs) are highly activated effector cells contributing to tissue damage and ultimately organ failure. Herein, we present preliminary data that instead, KITs express multiple inhibitory receptors and behave dysfunctionally with reduced cytokine production and proliferative capacity, driven by the expression of an “exhausted” transcriptional signature. Our data suggests that the tissue parenchyma has the capability to suppress T cell responses and limit damage to self. This proposal will allow us to expand on our novel finding that T cell exhaustion occurs in target organs in the setting of autoimmunity and explore how best to take advantage of this phenomenon to ameliorate disease. Aim 1 addresses the following questions: (1) What are the kinetics of T-cell exhaustion? Specifically, are early infiltrating cells activated and become exhausted over time, or does exhaustion occur simultaneously with or even before infiltration? and (2) Is T cell exhaustion observed in other organs damaged in lupus? The answers will reveal how exhaustion evolves and whether all tissues regulate infiltrating T cells similarly. This information will elucidate how parenchymal tissues regulate autoimmune attack, which in turn should help in finding tissue-specific regulatory defects in SLE as well in designing ways to modulate tissue regulation to treat SLE. Aim 2 addresses whether parenchymal IFN-gamma responses and PD-L1 expression in the tissue regulate the T cell exhaustion phenotype observed in SLE. Using a novel IFN-gamma receptor deficient mouse and bone marrow chimera experiments we aim to address how the renal parenchyma induces T cell exhaustion. Aim 3 addresses relevance to human disease by asking whether markers of T cell exhaustion are prognostic of disease outcomes. While there is indirect evidence to suggest that this is the case, the studies we propose will deliver a direct approach to assess the potential prognostic uses of markers of T-cell exhaustion. The long-term objective of this proposal is to improve patient care by identifying therapeutic targets and prognostic indicators for SLE patients. This proposal will provide critical insights into how best to promote tissue-resident T cell exhaustion and thus protect target organs from damage. Exhausted cells differ metabolically and otherwise from activated T cells and thus might be selectively targeted, while limiting generalized immunosuppression. Completion of these aims will advance our knowledge in a newly emerging field and lay the groundwork for numerous future investigations. These paths of research include clinical (prognostic factor identification), translational (novel drug development), and basic (mechanisms of T cell signaling in end-organs) studies.