Down-regulation of Th2 responses by Brucella abortus, a strong Th1 stimulus, correlates with alterations in the B7.2-CD28 pathway

Down-regulation of the Th2-like response induced by ovalbumin-alum (OVA/alu m) immunization by heat-killed Brucella abortus was not reversed by anti-IL -12 antibody treatment or in gamma interferon (IFN-gamma) knockout mice, su ggesting that induction of Th1 cytokines was not the only mechanism involve d in the B. abortus-mediated inhibition of the Th2 response to OVA/alum. Th e focus of this study was to determine whether an alternative pathway invol ves alteration in expression of costimulatory molecules, First we show that the Th2-like response to OVA/alum is dependent on B7.2 interaction with li gand since it can be abrogated by anti-B7.2 treatment. Expression of costim ulatory molecules was then studied in mice immunized with OVA/alum in the a bsence or presence of B. abortus. B7.2, but not B7.1, was up-regulated on m ouse non-T and T cells following immunization,vith B. abortus. Surprisingly , B. abortus induced down-regulation of CD28 and upregulation of B7.2 on mu rine CD4(+) and CD8(+) T cells. These effects on T cells were maximal for C D28 and B7.2 at 40 to 48 h and were not dependent on interleukin-12 (IL-12) or IFN-gamma. On the basis of these results, we propose that the IL-12/IFN -gamma-independent inhibition of Th2 responses to OVA/alum is secondary to the effects of B. abortus on expression of costimulatory molecules on T cel ls. We suggest that down-regulation of CD28 following activation inhibits s ubsequent differentiation of Th0 into Th2 cells. In addition, decreased exp ression of CD28 and increased expression of B7.2 on T cells would favor B7. 2 interaction with CTLA-4 on T cells, and this could provide a negative sig nal to developing Th2 cells.