THEMIS is required for pathogenesis of cerebral malaria and protection against pulmonary tuberculosis

We identify an N -ethyl- N -nitrosourea (ENU)-induced I23N mutation in the THEMIS protein that causes protection against experimental cerebral malaria (ECM) caused by infection with Plasmodium berghei ANKA. Themis I23N homozygous mice show reduced CD4 + and CD8 + T lymphocyte numbers. ECM resistance in P. berghei ANKA-infected Themis I23N mice is associated with decreased cerebral cellular infiltration, retention of blood-brain barrier integrity, and reduced proinflammatory cytokine production. THEMIS I23N protein expression is absent from mutant mice, concurrent with the decreased THEMIS I23N stability observed in vitro . Biochemical studies in vitro and functional complementation in vivo in Themis I23N/ + : Lck −/ + doubly heterozygous mice demonstrate that functional coupling of THEMIS to LCK tyrosine kinase is required for ECM pathogenesis. Damping of proinflammatory responses in Themis I23N mice causes susceptibility to pulmonary tuberculosis. Thus, THEMIS is required for the development and ultimately the function of proinflammatory T cells. Themis I23N mice can be used to study the newly discovered association of THEMIS (6p22.33) with inflammatory bowel disease and multiple sclerosis.