Mechanisms Underlying Immune Signatures in Autoimmunity

Currently, the Long lab has three interdependent, collaborative projects focused on understanding how tolerance is lost in autoimmunity. Gaining a better understanding of the disease-related causes and consequences of defective cytokine signaling (project 1) may lead to development of more sensitive biomarkers (project 2) and more targeted therapies that promote tolerance (project 3):

1. How May Altered Cytokine Responses Be Involved In Loss Of Tolerance? 

The Long lab is focusing on common gamma chain cytokine signaling pathways in type 1 diabetes (T1D) as compared to other autoimmune diseases including multiple sclerosis (MS) and systemic lupus erythematosus (SLE). We are using genotype-phenotype and functional studies to discover the underlying molecular mechanisms of defective signaling and the physiological impact of this dysregulation on lymphocytes.

Working with collaborators, we are involved in understanding how treatments targeting cytokine pathways may promote tolerance in autoimmune patients.

2. What Factors Promote Exhausted CD8 T Cells, a Cell Type Associated With Better Outcome in T1D? 

Clinical signs of autoimmune disease often occur long after damage of the organ thereby limiting potential to intervene or reverse disease progression. Thus, it is important to be able to identify deleterious autoimmune responses before the effects of this damage become clinically apparent. In parallel, when treating disease it would be helpful to better understand whether the pathogenic cells are reduced and protective cells are enhanced. With Dr. James and Dr. Cerosaletti the Long lab is discovering and tracking T cell signatures in T1D subjects who have different rates of disease progression. These studies have led to the discovery that exhausted CD8 T cells are increased in subjects with a slower course of disease. In our own studies and in collaboration with  Dr. Buckner, we are determining when T cell signatures of T1D appear by studying subjects at-risk for developing T1D over time. Lastly, working with Dr. Speake and the JDRF Core Assay Validation group, we are establishing whether a composite biomarker (multiple assays) will be more effective in defining autoimmune disease progression.

Following-up on the key discovery that exhausted CD8 T cells are associated with better outcome, we are discovering factors that may promote exhaustion in T1D. This project overlaps with our third goal of discovering better ways to treat autoimmunity and our first goal of understanding how cytokines may modulate tolerance.

3. Can We Better Treat Autoimmunity By Understanding The Mechanisms Of Action Of Therapies In The Context Of Each Autoimmune Patient? 

Through the HIP Core collaborative work with the ITN and TrialNet and work with Dr. Linsley in Systems Immunology, we have discovered unique phenotypes and “signatures” that track with responders, and nonresponders, to therapy. We are using in vitro cultures and extensive cellular immune phenotyping (CyTOF and 18-color flow) paralleled with transcriptional analyses and functional assays to reveal underlying mechanism of response in each patient.