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/alum) immunization by heat-killed Brucella abortus was not reversed by anti-IL-12 antibody treatment or in gamma interferon (IFN-gamma) knockout mice, suggesting that induction of Th1 cytokines was not the only mechanism involved in the B. abortus-mediated inhibition of the Th2 response to OVA/alum. The focus of this study was to determine whether an alternative pathway involves alteration in expression of costimulatory molecules. First we show that the Th2-like response to OVA/alum is dependent on B7.2 interaction with ligand since it can be abrogated by anti-B7.2 treatment. Expression of costimulatory molecules was then studied in mice immunized with OVA/alum in the absence or presence of B. abortus. B7.2, but not B7.1, was up-regulated on mouse non-T and T cells following immunization with B. abortus. Surprisingly, B. abortus induced down-regulation of CD28 and up-regulation of B7.2 on murine CD4(+) and CD8(+) T cells. These effects on T cells were maximal for CD28 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 cells. We suggest that down-regulation of CD28 following activation inhibits subsequent differentiation of Th0 into Th2 cells. In addition, decreased expression 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 signal to developing Th2 cells.
Agranovich
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I
Laboratory of Plasma Derivatives, Division of Hematology, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland 20852, USA.
Scott
D E
DE
Terle
D
D
Lee
K
K
Golding
B
B
D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis*; D002003:Brucella abortus / Q000276:immunology*; D018106:CD28 Antigens / Q000096:biosynthesis*; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
D018122:B7-1 Antigen; D018106:CD28 Antigens; D018664:Interleukin-12; D007371:Interferon-gamma; D010047:Ovalbumin