ITK NEGATIVELY REGULATES INDUCTION OF T-CELL PROLIFERATION BY CD28 COSTIMULATION

CD28 is a cell surface molecule that mediates a costimulatory signal c rucial for T cell proliferation and lymphokine production. The signal transduction mechanisms of CD28 are not well understood. Itk, a nonrec eptor protein tyrosine kinase specifically expressed in T cells and ma st cells, has been implicated in the CD28 signaling pathway because of reports that it becomes phosphorylated on tyrosines and associates wi th CD28 upon cross-linking of the cell surface molecule. To determine whether Itk plays a functional role in CD28 signaling, we compared T c ells from Itk-deficient mice and control mice for their responses to C D28 costimulation. T cells defective in Itk were found to be fully com petent to respond to costimulation. Whereas the CD3-mediated prolifera tive response tvas severely compromised in the absence of Itk, the cal cineurin-independent CD28-mediated response was significantly elevated when compared with cells from control animals. The augmented prolifer ation was not due to increased production of interleukin-2. The result s suggest that Itk has distinct roles in the CD3 versus the CD28 signa ling pathways. By negatively regulating the amplitude of signaling upo n CD28 costimulation, Itk may provide a means for modulating the outco me of T cell activation during development and during antigen-driven i mmune responses.