ANERGY OF T(H)0 HELPER T-LYMPHOCYTES INDUCES DOWN-REGULATION OF T(H)1 CHARACTERISTICS AND A TRANSITION TO A T(H)2-LIKE PHENOTYPE

Mature CD4(+) helper T lymphocytes have been categorized into two major functional phenotypes, T(H)1 and T(H)2, which produce distinct arrays of lymphokines and which are thought to arise from a pluripotential precursor cell termed T(H)0. Clonal anergy can be induced in T(H)1 clones by stimulating via the T cell receptor (TCR) complex in the absence of a costimulator molecule; however, anergy has been difficult to demonstrate in T(H)2 clones. We show here that treatment of cloned T(H)0 lines with anergizing stimuli results in the selective loss of T(H)1 characteristics and retention of a T(H)2 phenotype. Treated cells exhibit a substantial reduction in interleukin 2 (IL-2) production and antigen-specific cytolytic activity, but retain comparable IL-4 and IL-5 production in response to restimulation via the TCR complex. T(H)0 clones exposed to anergizing stimuli also increase in size, thus morphologically resembling T(H)2 cells. The signaling characteristics of these cells also are altered, in that they exhibit an elevated basal level of intracellular free calcium which fails to increase significantly with subsequent restimulation, reminiscent of the signaling characteristics of T(H)2 cells. ''Anergized'' T(H)0 clones thus share several functional, morphologic, and physiologic properties with cells of the T(H)2 phenotype, suggesting that T(H)2 cells may arise when T(H)0 cells are stimulated via the TCR complex in the absence of a putative costimulator molecule.