T cells in Autoimmune Disease

Adkins & Roopenian Spotlight

Derry Roopenian & Elisabeth Adkins and spleens from normal mice and mice with lupus

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The primary purpose of the immune system is to provide organisms with a critical line of defense against foreign infectious agents, such as bacteria and viruses. When operating normally, this highly complex system is able to discern infected cells from the organism's own healthy tissues. However, autoimmune diseases can arise when the immune system looses the ability to discriminate foreign from self and attacks normal tissues. Genetics PhD student Elisabeth Adkins and her adviser, Derry Roopenian, PhD seek to understand how a key cell type – T-follicular helper (TFH) ¬ cells – fit into normal immunity and autoimmune diseases.

TFH cells are a specialized activated CD4+ T helper cells that are only partially understood. Their most active product is the cytokine, Interleukin 21 (IL21), which potently drives B cells to proliferate, differentiate and secrete antibodies. Under normal conditions, these antibodies provide protective immunity to infections. However, research in mouse models and human patients with certain autoimmune diseases has revealed increased activity of TFH. This research shows that TFH cells, largely through their production of IL21, cause B cells to produce autoantibodies that attack the patients own tissues and cause severe disease symptoms.

Elisabeth's first research goal is to fill a major gap in our current knowledge: the mechanisms by which TFH develop and produce IL21 under normal non-disease conditions. She has been utilizing an IL21-reporter mouse model in which IL21 is revealed by sensitive fluorescent techniques. This model allows her to readily track cells expressing IL21. Through this work she has identified a novel IL21 expressing population that represents the earliest precursors of TFH. She has termed these precursors nascent TFH. Her work is now applying a variety of approaches to define the genes and pathways that regulate the development of nascent TFH and how they differentiate into fully functional mature TFH cells.

Elisabeth's second goal is to understand how the normal development of TFH and their production of IL21 is altered in the autoimmune diseases systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), in which TFH and IL21 may play a critical role. Using mouse models for SLE and RA, she has found that IL21-producing TFH are greatly increased and required for disease development. Elisabeth is now testing the hypothesis that this increase is caused by the loss of regulatory constraints that normally limit nascent TFH cells and their differentiation to pathological mature TFH cells. Her ultimate goal is to define the genetic and cellular mechanisms through which TFH cause autoimmune diseases and use this information to identify new therapeutic interventions that regulate this process.

Elisabeth is a member of JAX track within the Genetics program and is conducting her thesis work at The Jackson Laboratory in Bar Harbor, ME. 

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