Tired T cells

Sherman was senior author of a new study examining this phenomenon and the protein responsible for hampering the immune system. The study, “PTPN22 contributes to exhaustion of T cell lymphocytes during chronic viral infection,” appeared in Proceedings of the National Academy of Sciences.

The protein in question is PTPN22 (protein tyrosine phosphatase nonreceptor type 22 gene), which is expressed in all immune cells. As noted in the paper, PTPN22 is responsible for “suppression of T cell receptor signaling and promoting efficient production of type I interferons (IFN-I) by myeloid cells.”

Individuals who have an altered form of this protein have a significantly increased risk for type 1 diabetes and other autoimmune diseases; the Genetics Home Reference of the U.S. National Library of Medicine cites rheumatoid arthritis, systemic lupus erythematosus and Graves disease as conditions that arise from abnormal copies of this gene and its protein.

Given how PTPN22 affects the immune system, Sherman and her colleagues wondered if a lack of the protein could consequently prevent the immune system from triggering T cell exhaustion. They sought to answer that question using mouse models infected with a clone of lymphocytic choriomeningitis virus (LCMV), which results in chronic infections similar to HIV and hepatitis. Mice without PTPN22 were able to clear the LCMV infections, but mice with PTPN22 presented with chronic infection and signs of T cell exhaustion.

“The animals deficient in the PTPN22 protein shrugged off the virus very quickly, rather than having the immune system shut down the way it normally does when it encounters this virus,” added Sherman.

“PTPN22 increases the production of IFN-β following infection, resulting in increased expression of the cAMP response element modulator (CREM) in CD4 T lymphocytes. CREM prevents production of IL-2, thereby contributing to T cell exhaustion and chronic viral infection … Mice deficient in PTPN22 resist chronic viral infection with lymphocytic choriomeningitis virus clone 13 (LCMV cl13),” the abstract notes. “The numbers and function of viral-specific CD4 T lymphocytes is greatly enhanced, whereas expression of the IFNβ-induced IL-2 repressor, cAMP-responsive element modulator (CREM) is reduced. Reduction of CREM expression in wild-type CD4 T lymphocytes prevents the loss of IL-2 production by CD4 T lymphocytes during infection with LCMV cl13.”

Moving forward, the team plans to study PTPN22's role in other cells as well, with Sherman noting that “We have to understand what’s going on so we can take advantage of that to make new types of drugs.”

Other authors of this study included Christian J. Maine, John R. Teijaro and Kristi Marquardt, all of TSRI at the time of the study.