Introduction: Translationally controlled tumor protein (TCTP) is significantly induced in naïve T cells following T cell antigen receptor (TCR) stimulation, and is required for the blastogenesis and proliferation of activated T cells. However, its role during T cell activation remains unclear.
Methods: Polysome profiling, protein interaction, mRNA and protein expression were analyzed for control and TCTP-deficient T cells following TCR stimulation. T cell differentiation responses were also analyzed using control and T-cell specific TCTP-deficient mice. Statistical analysis was performed with unpaired, two-tailed Student’s t test.
Results: Here we demonstrate that TCTP co-fractionates with the 40S ribosome subunits loaded with the initiation factors, and that deletion of TCTP results into an abnormal polysome profile with a markedly diminished level of the 80S monosome and the appearance of the half-mers in the polyribosome fractions. Consistently, TCTP deficiency results in reduced synthesis of a large subset of proteins in TCR-stimulated T cells. Notably, some of these affected proteins are components of the translation machinery itself, whose reduced synthesis in TCTP-deficient T cells is mainly at the mRNA translation level. TCTP directly interacts with the translation initiation complex and TCTP mutants defective in forming such complex fail to rescue the proliferation defect of the TCTP-deficient T cells, suggesting that TCTP regulates T cell proliferation at least partially at the mRNA translation initiation step. Last, mutant mice with conditional knockout of TCTP in T cells manifested impaired Th1 and Th2-mediated immune responses, which correlated with impaired IFNg and IL-4 mRNA translation during T cell differentiation to Th1 and Th2 subsets, respectively.
Conclusion: This study reveals a novel role of TCTP in the mRNA translation initiation step, which is essential for both T cell proliferation and differentiation.