THE MECHANISM OF IN-VITRO T-HELPER CELL-TYPE-1 TO T-HELPER CELL-TYPE 2 SWITCHING IN HIGHLY POLARIZED LEISHMANIA MAJOR-SPECIFIC T-CELL POPULATIONS

We have previously demonstrated that highly polarized CD4(+) Th1 cells isolated from Leishmania major-infected mice could be switched to a T h2-like phenotype when cultured for 1 wk in the presence of APC, L. ma jor Ag, and IL-4, suggesting that the reversion of a differentiated Th response could occur at the population level. To investigate the cell ular basis for this population switch, CD4(+) lymph node cells from Th 1-polarized L. major-infected mice were separated into two subsets bas ed on the level of expression of L-selectin (Mel-14), and each subset was stimulated with APC and IL-2 for 1 wk in the presence or the absen ce of IL-4, Mel-14(low) T cells contained all of the initial Th1 activ ity and retained their Th1 phenotype when cultured with IL-4. In contr ast, Mel-14(high) T cells did not produce cytokines upon challenge wit h L. major Ag, but gave rise to a Th2-like population after culture wi th IL-4. Thus, the newly induced Th2 population was derived from undif ferentiated cells distinct from the Thl cells present in the starting population. This undifferentiated Th precursors could be induced to de velop into either Th1 or Th2 cells and were not recent thymic emigrant s as they were present in mice thymectomized before infection, These e xperiments show that a chronically stimulated and highly polarized Th1 population consisted of both precursor T cells able to differentiate into Th2 cells and cells fully differentiated into Th1 cells that coul d not be induced to switch their pattern of cytokine production.