SELECTIVE DEVELOPMENT OF T-HELPER (TH)2 CELLS INDUCED BY CONTINUOUS ADMINISTRATION OF LOW-DOSE SOLUBLE-PROTEINS TO NORMAL AND BETA-2-MICROGLOBULIN-DEFICIENT BALB C MICE/

Continuous administration of soluble proteins, delivered over a 10-d p eriod by a mini-osmotic pump implanted subcutaneously, induces a long- lasting inhibition of antigen-specific T cell proliferation in lymph n ode cells from BALB/c mice subsequently primed with antigen in adjuvan t. The decreased T cell proliferative response is associated with a do wn-regulation of the T helper cell (Th)1 cytokines interleukin (IL)-2 and interferon (IFN)-gamma and with a strong increase in the secretion of the Th2 cytokines IL-4 and IL-5 by antigen-specific CD4(+) T cells . This is accompanied by predominant inhibition of antigen-specific an tibody production of IgG2a and IgG2b, rather than IgG1 isotype. Intere stingly, inhibition of Th1 and priming of Th2 cells is also induced in beta 2-microglobulin-deficient BALB/c mice, indicating that neither C D8(+) nor CD4(+) NK1.1(+) T cells, respectively, are required. The pol arization in Th2 cells is stably maintained by T cell Lines, all compo sed of CD4(+)/CD8(-) cells expressing T cell receptor for antigen (TCR )alpha/beta chains, derived from BALB/c mice treated with continuous a ntigen administration, indicating that they originate from Th2 cells f ully differentiated in vivo. This polarization is induced in BALB/c mi ce by continuous administration of any protein antigen tested, includi ng soluble extracts from pathogenic microorganisms. Priming of Th2 cel ls is dose dependent and it is optimal for low rather than high doses of protein. Blocking endogenous IL-4 in vivo inhibits expansion of ant igen-specific Th2 cells, but does not restore IFN-gamma production by T cells from mice treated with soluble antigen, indicating the involve ment of two independent mechanisms. Consistent with this, Th2 cell dev elopment, but not inhibition of Th1 cells, depends on non-major histoc ompatibility complex genetic predisposition, since the Th2 response is amplified in BALB/c as compared to DBA/2, C3H, or C57BL/6 mice wherea s inhibition of the Th1 response is induced by soluble protein adminis tration in any mouse strain tested. These findings support the hypothe sis that continuous release of low amounts of protein antigens from pa thogenic microorganisms may polarize the immune response toward a Th2 phenotype in susceptible mouse strains.