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

Abstract

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. ThemisI23N homozygous mice show reduced CD4+ and CD8+ T lymphocyte numbers. ECM resistance in P. berghei ANKA-infected ThemisI23N mice is associated with decreased cerebral cellular infiltration, retention of blood-brain barrier integrity, and reduced proinflammatory cytokine production. THEMISI23N protein expression is absent from mutant mice, concurrent with the decreased THEMISI23N stability observed in vitro. Biochemical studies in vitro and functional complementation in vivo in ThemisI23N/+: Lck-/+ doubly heterozygous mice demonstrate that functional coupling of THEMIS to LCK tyrosine kinase is required for ECM pathogenesis. Damping of proinflammatory responses in ThemisI23N mice causes susceptibility to pulmonary tuberculosis. Thus, THEMIS is required for the development and ultimately the function of proinflammatory T cells. ThemisI23N mice can be used to study the newly discovered association of THEMIS (6p22.33) with inflammatory bowel disease and multiple sclerosis.