Interchangeability of Themisl and Themis2 in Thymocyte Development Reveals Two Related Proteins with Conserved Molecular Function.

Themisl, a recently identified T cell protein, has a critical function in the generation of mature CD4+CD8- and CD4-CD8+ (CD4 and CD8 single-positive [SP]) thymocytes and T cells. Although Themisl has been shown to bind to the adaptor proteins LAT and Grb2, previous studies have yielded conflicting results regarding whether thymocytes from Themisl-/- mice exhibit TCR-mediated signaling defects. In this study, we demonstrate that, in the absence of Themisl, TCR-mediated signaling is selectively impaired in CD4 SP and CD8 SP thymocytes but is not affected in CD4+CD8+ double-positive thymocytes despite high expression of Themisl in double-positive thymocytes. Like Themisl, Themis2, a related member of the Themis family, which is expressed in B cells and macrophages, contains two conserved cysteine-based domains, a proline-rich region, and a nuclear localization signal. To determine whether Themisl and Themis2 can perform similar functions in vivo, we analyzed T cell development and TCR-mediated signaling in Themisl-/- mice reconstituted with either Themisl or Themis2 transgenes. Notably, Themisl and Themis2 exhibited the same potential to restore T cell development and TCR-mediated signaling in Themisl-/-mice. Both proteins were tyrosine phosphorylated and were recruited within Grb2 signaling complexes to LAT following TCR engagement. These results suggest that conserved molecular features of the Themisl and Themis2 proteins are important for their biological activity and predict that Themisl and Themis2 may perform similar functions in T and B cells, respectively. The Journal of Immunology, 2012, 189: 1154-1161. [ABSTRACT FROM AUTHOR]