NON-MHC-LINKED TH2 CELL-DEVELOPMENT INDUCED BY SOLUBLE-PROTEIN ADMINISTRATION PREDICTS SUSCEPTIBILITY TO LEISHMANIA-MAJOR INFECTION

Continuous administration of soluble protein Ag followed by immunizati on with the same Ag in adjuvant results in the selective development o f Ag-specific CD4(+) Th2 cells in both normal and beta(2)-microglobuli n-deficient BALB/c mice. In addition to chronic administration by mini -osmotic pump, single bolus i.p., but not i.v., injection of protein A g induces Th2 cell expansion. Strong Th2 cell priming depends on a non -MHC-linked genetic polymorphism. It is observed in all congenic strai ns on BALB background tested, BALB/c, BALB/b, and BALB/k, but not in M HC-matched strains on disparate genetic background, B10.D2, C57BL/6, a nd C3H. DBA/2 mice appear to have an intermediate phenotype, as shown by their weaker capacity to mount Th2 responses as compared with BALB/ c mice after soluble Ag administered by either mini-osmotic pumps or s ingle bolus i.p. Conversely, induction of Th1 cell unresponsiveness by soluble protein is observed in any mouse strain tested, following any mode of Ag administration. These data demonstrate that non-MHC-linked genetic polymorphism controls the priming of Th2 but not the inhibiti on of Th1 cells induced by administration of soluble protein. The patt ern of Th2 responses in these different strains is predictive of disea se outcome following Leishmania major infection and supports the hypot hesis that systemic Ag presentation in the absence of strong inflammat ory signals may represent an important stimulus leading to selective T h2 cell development in susceptible mouse strains.