Immunobiology

Killer T cells, though a subtype themselves, can transform into even more specialized subtypes. Little was known about what influences this further differentiation until Professor Susan Kaech, Associate Professor Diana Hargreaves, co-first authors Bryan McDonald and Brent Chick, and colleagues endeavored to unravel this T cell differentiation mystery. What they discovered was that a protein complex called cBAF can open or close genetic “doors” to control T cell fate. Their findings illuminate how T cells fight and remember infections, and inspire the development of more effective vaccines and cancer therapeutics.

Associate Professor Dmitry Lyumkis and colleagues, in collaboration with the National Institutes of Health, discovered the molecular mechanisms by which human immunodeficiency virus (HIV) becomes resistant to Dolutegravir, one of the most effective, clinically used antiviral drugs for treating the infection. The new study reveals how changes to the 3D structures of integrase, an HIV protein, can lead to Dolutegravir resistance and how other compounds may be able to overcome this resistance.

Since helper T cells lead the fight against infection and can promote the activity of killer T cells, when researchers were looking to explain wasting—the loss of fat and muscle that can occur during infection—they hypothesized the two T cell types may be cooperating. Professor Janelle Ayres, first author Samuel Redford, and colleagues discovered the wasting response to infection with the bacteria T. brucei in mice occurs in two phases, each regulated by different T cell subtypes. While fat loss did not benefit the fight against infection, muscle loss did—a surprising clue that some wasting may help manage illness. The findings can inform the development of more effective therapeutics that spare people from wasting and increase our understanding of how wasting influences survival and morbidity across infections, cancers, chronic illnesses, and more.

Professor Susan Kaech, co-first authors Dan Chen and Siva Karthik Varanasi, and colleagues found that helper T cells play a crucial role in the success of the immunotherapy treatment anti-CTLA-4 in mice with glioblastoma, the most common and deadly form of brain cancer. The immunotherapy’s success depended on helper T cells pairing up with brain-resident immune cells called microglia—demonstrating the value of the immune system’s quilted connections. The findings show the benefit of harnessing the body’s own immune cells to fight brain cancer and could lead to more effective immunotherapies for treating brain cancer in humans.