James Allison of the MD Anderson Cancer Center has made key discoveries on the regulation of T cell activation and modulation, including identification and characterization of the T cell antigen receptor and the T cell coreceptors CD28 and cytotoxic T lymphocyte antigen-4 (CTLA-4). He was awarded the 2015 Lasker~DeBakey Clinical Medical Research Award in honor of his discovery and subsequent development of CTLA-4–targeted monoclonal antibody therapy to unleash the immune response to cancer. In an interview with JCI Editor at Large Ushma Neill, Allison discusses his decision to pursue a PhD instead of an MD and his early experiences in applying biochemical techniques to immunological questions. Additionally, Allison talks about the process of moving anti–CTLA-4 therapy into the clinic.
Infection with group A Streptococcus (GAS) causes the common and treatable pharyngitis known as strep throat; however, these infections are also associated with autoimmune diseases of the central nervous system (CNS). A subset of children are at risk of developing pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), which are characterized by an abrupt onset of abnormal behaviors. In murine models, GAS has been shown to induce a robust Th17 response in nasal-associated lymphoid tissues. In this episode, Pat Cleary and Dritan Agalliu discuss their collaboration to investigate the link between the generation of GAS-specific Th17 cells and CNS autoimmunity. They determined that multiple intranasal GAS challenges in mice promotes migration and persistence of GAS-specific Th17 cells to the brain, leading to blood-brain barrier (BBB) breakdown and autoantibody access to the CNS. Moreover, they identified GAS-specific Th17 cells in the tonsils of patients naturally exposed to GAS. Together, these data provide insights into the immunopathology underlying GAS-associated neurological complications.
The affinity that B cells have for antigen is increased through an iterative process known as affinity maturation. This process involves the cycling of B cells cycle between somatic hypermutation and proliferation in the germinal center (GC) dark zone (DZ), allowing the acquisition of mutations that enhance antigen affinity, and clonal selection in the GC light zone (LZ). The oncogenic microRNA miR-155 is required for efficient affinity maturation and GC maintenance; however, the underlying molecular mechanisms are unclear. In this episode, Rinako Nakagawa and Elena Vigorito discuss their work, which reveals that miR-155 is highly expressed in positively selected c-MYC+ LZ B cells and inhibits JARID2 to prevent apoptosis of positively selected B cells. Together, the results of this study provide important insight in the GC response and how c-MYC and miR-155 may collaborate as oncogenes.
The pulmonary disease tuberculosis (TB) is a global health problem that results from Mycobacterium tuberculosis (Mtb) infection. As parasitic helminth worms are endemic to areas with high rates of TB, helminths are thought to enhance susceptibility to Mtb. In this episode, Shabaana Khader and colleagues demonstrate that helminth coinfection exacerbates TB by promoting formation of arginase-1-expressing inflammatory granulomas, resulting in increased lung damage. Moreover, inflammatory phenotypes associated with coinfection were reversed in a murine co-infection model by treatment with anti-helminthic agents. This study provides mechanistic insight into the link between helminth coinfection and TB disease severity.
Oliver Smithies of the University of North Carolina at Chapel Hill was awarded the 2007 Nobel Prize in Physiology or Medicine for pioneering homologous recombination of transgenic DNA, which allowed for the creation of knockout and transgenic mice. Smithies’ lab created the first murine models of cystic fibrosis. He has also identified genetic factors involved in heart disease, atherosclerosis, and other disorders. In an interview with JCI Editor-at-large Ushma Neill, Dr. Smithies discusses his early interest in science, including his propensity for tinkering, the invention of starch gel electrophoresis, and his first molecular genetic studies of haptoglobin. Smithies also describes the three year development of his protocol for genetic transformation of human cells, his feelings on winning the Nobel Prize, and his admiration for Johann Sebastian Bach.