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CD40-Deficient Mice GEORG A Proc. Natl. Acad. Sci. USA Vol. 93, pp. 4994-4998, May 1996 Immunology Induction of alloantigen-specific tolerance by B cells from CD40-deficient mice GEORG A. HOLLXNDER*t, EMANUELA CASTIGLIt, ROBERT KULBACKI§, MICHAEL SU*, STEVEN J. BURAKOFF*, JOSEI-CARLOS GUTIERREZ-RAMOS§, AND RAIF S. GEHAt *Division of Pediatric Oncology, Dana-Farber Cancer Institute, Department of Pediatrics, tDivision of Immunology, The Children's Hospital, Department of Pediatrics, §Center for Blood Research, Harvard Medical School, Boston, MA 02115 Communicated by Frederick W Alt, The Children's Hospital, Boston, MA, January 22, 1996 (received for review November 17, 1995) ABSTRACT Interaction between CD40 on B cells and The capacity of B cells to provide ligands for T-cell specific CD40 ligand molecules on T cells is pivotal for the generation costimulatory molecules determines the outcome of T-cell of a thymus-dependent antibody response. Here we show that activation. Resting B cells express only limited amounts of B cells deficient in CD40 expression are unable to elicit the costimulatory molecules compared to activated B cells (11) proliferation of allogeneic T cells in vitro. More importantly, and are thus ineffective as antigen presenting cells (12). This mice immunized with CD40-1- B cells become tolerant to concept has also been demonstrated in vivo. For instance, allogeneic major histocompatibility complex (MHC) antigens monovalent rabbit anti-mouse IgD when presented by small as measured by a mixed lymphocyte reaction and cytotoxic resting B cells rendered mice tolerant to rabbit Ig (13). T-cell assay. The failure of CD40-'- B cells to serve as antigen Polyclonal activation of antigen presenting B cells (e.g., by presenting cells in vitro was corrected by the addition of crosslinking with divalent rabbit anti-mouse IgD) prevented anti-CD28 mAb. Moreover, lipopolysaccharide stimulation, the induction of tolerance (13). Injection of resting allogeneic which upregulates B7 expression, reversed the inability of B cells has however failed to induce tolerance to allogeneic CD40-- B cells to stimulate an alloresponse in vitro and major histocompatibility complex (MHC) molecules, the prin- abrogated the capacity of these B cells to induce tolerance in cipal T-cell targets in an allogeneic immune response (14). This vivo. These results suggest that CD40 engagement by CD40 may be due to the high frequency of allospecific T cells and/or ligand expressed on antigen-activated T cells is critical for the to in vivo activation of the transferred B cells following their upregulation of B7 molecules on antigen-presenting B cells recognition by host T cells. If the latter explanation is correct, that subsequently deliver the costimulatory signals necessary in vivo tolerance should be induced when allogeneic B cells are for T-cell proliferation and differentiation. Our experiments incapable of providing the costimulatory signal essential for suggest a novel strategy for the induction of antigen-specific initiation of T-cell activation. To test this hypothesis, we have tolerance in vivo. determined the capacity of CD40-deficient B cells to elicit an allogeneic response in vitro and in vivo. Two antigen nonspecific ligand receptor systems have been distinguished that mediate efficient activation of T and B cells. MATERIALS AND METHODS The first system is characterized by the interactions of CD28 and CTLA-4 on T cells with their physiological counter Animals. The CD40-/- mice were generated at the Center receptors, the B7 molecules, expressed on B cells and other for Blood Research by a targeting construct eliminating exons antigen presenting cells (reviewed in ref. 1). CD28 is found 7, 8, and 9 of CD40 (15). Mutant embryonic stem cells from both on resting and activated T cells, while CTLA-4 is ex- the Ji line heterozygous for CD40 gene-targeting were used pressed only after successful stimulation of T cells (2). The B7 for injection into C57BL/6 blastocysts. Chimeric founder mice family of receptors consists at present of two cloned molecules, were mated with C57BL/6 mice and inbreeding of the het- B7.1 and B7.2, and a putative third member, B7.3 (3). Al- erozygous mice resulted in mice homozygous for the CD40 though crosslinking of CD28 alone does not deliver an acti- deficiency. The phenotype of these knockout mice is identical vation signal to resting T cells, stimulation of preactivated T to the one of CD40-/- mice obtained by recombination- cells with anti-CD28 monoclonal antibodies (mAb) results in activating gene-2-deficient blastocyst complementation (15). a vigorous proliferative response and marked secretion of Wild-type C57BL/6 (H-2b), B10.BR (H-2k), and BALB/c multiple lymphokines (1). Conversely, prevention of signaling (H-2d) mice were obtained from The Jackson Laboratory. through CD28 in a cognate T-B cell interaction using Fab Cell Isolation. T and B cells were isolated from spleen and fragments of an anti-CD28 antibody results in abrogation of lymph nodes by magnetic cell separation using positive selec- antigen-specific proliferation and in failure to respond to a tion by Thy 1.2 or B220 (CD45R) magnetic beads, respectively subsequent antigenic challenge (4, 5). (Milteny, Biotec, Sunnyvale, CA). Isolated cells were typically The second receptor ligand system important for lympho- >97% pure as determined by flow cytometry and appeared cyte activation involves the binding of the B-cell antigen CD40 viable by exclusion of trypan blue and by forward/side scatter to its physiological ligand, CD40 ligand (CD40L) expressed on analysis. Purified splenic B cells for in vivo experiments were activated T cells. Ligation of CD40 on B cells mediates a wide obtained from single-cell suspensions after plastic adherence range of biological activities including homotypic adhesion, and two rounds of treatment with anti-Thy 1.2 mAb (clone proliferation, expression of costimulatory molecules B7.1 and 30H-12) at 4°C followed by an incubation with low TOX-M B7.2, and Ig isotype switching (6-9). CD40L is transiently rabbit complement (Cedarlane Laboratories). B-cell purity expressed predominantly on CD4+ T cells after T- cell receptor was regularly >90%. (TCR) triggering and independently of CD28/CTLA-4 co- stimulation (7, 10). Abbreviations: APC, antigen presenting cell; CD40L, CD40 ligand; LPS, lipopolysaccharide; MHC, major histocompatibility complex; TCR, T-cell receptor. The publication costs of this article were defrayed in part by page charge tPresent address: Pediatric Immunology, Department of Research, payment. This article must therefore be hereby marked "advertisement" in Kantonsspital and The University Children's Hospital, Basel, CH- accordance with 18 U.S.C. §1734 solely to indicate this fact. 4031 Switzerland. 4994 Downloaded by guest on September 29, 2021 Immunology: Hoildnder et al. Proc. Natl. Acad. Sci. USA 93 (1996) 4995 Antibodies and Fusion Proteins. Antibodies against the 4 following molecules were obtained from PharMingen: CD3-E (clone 145-2C11), CD8a, CD28 (37.51), CD40L (MR1), B200 (CD45R; RA3-6B2), B7-1 (CD80; 1G10), B7-2 (CD86; GL1). 6 The expression of CD40 was detected by a CD40L-CD8a 3 x fusion protein (gift of P. Lane, Basel Institute for Immunology; E ref. 16) followed by staining with anti-CD8a mAb. Soluble CD40 (sCD40), a fusion protein consisting of the extracellular CL domain of human CD40 and the Fc portion of human IgG1 (17) 0.0 2 and murine CTLA-4/Ig (a generous gift from T. Strom, Beth Israel Hospital, Boston) were used for blocking studies in vitro. c0 Mixed Lymphocyte Reaction (MLR). Various numbers of irradiated (2000 rads) splenic B cells from wild-type or CD40-/- C57BL/6 mice (H-2b) were seeded into round bot- tom 96-well microtiter plates (Costar) as stimulators and a- cocultured with 1-2 x 105 purified T cells from BALB/c mice (H-2d) in RPMI 1640 medium supplemented with 10% fetal calf serum (Sigma), penicillin, streptomycin, and 2-mercapto- 0 2.5 5 7.5 10 ethanol (50 ,uM). Where indicated, mAb and fusion proteins (1 ,ug/ml) of different specificity were added to the MLR at the Stimulator cells [xl 04] onset of culture. For experiments with preactivated cells, purified B cells were stimulated for 24 hr with lipopolysaccha- FIG. 1. CD40-deficient B cells do not stimulate an allogeneic T-cell irradiation response in vitro. Irradiated purified B cells from spleen of wild-type ride (LPS) (20 ,ug/ml) prior to extensive washing, (-) and CD40-'- (O) C57BL/6 mice were cocultured with 2 x 105 (2000 rads), and seeding to 96-well microtiter plates. Prolif- purified BALB/c T cells in microtiter wells for 5 days. Proliferation eration was measured by incorporation of [3H]-thymidine was measured by [3H]-thymidine uptake during the last 16 hr of during the last 16 hr of a 5-day culture.The standard error for culture. This graph is representative of four independent experiments. each data point was less than 15% of the mean. Flow Cytometry. Purified B cells (5 x 105/200 ,ul) were CD40-/- B cells to stimulate an allogeneic response (data not cultured in vitro for 48 hr in 96-well round bottom plates either shown). in the presence of LPS (20 ,ug/ml; Sigma) or CD40L/CD8 We next investigated whether co-engagement of CD28 by chimeric protein (1 ,ug/ml), then analyzed by flow cytometry mAb can permit responder T cells to be activated by allogeneic for the surface expression of B220 (fluorescein isothiocyanate- CD40-deficient B cells. As shown in Fig. 2, addition of mAb labeled RA3-6B2), B7.1 (PE-labeled 1G10), and B7.2 (phos- against CD28 caused BALB/c T cells to proliferate in response phatidylethanolamine-labeled GL1) using a FACScan and to CD40-/- B cells. Importantly, in the presence of anti-CD28, LYSYS software (Becton Dickinson). the magnitudes of T-cell proliferation elicited by CD40-/- and In Vivo Immunization.
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