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Experimental Murine Schistosomiasis in the Absence of B7 Costimulatory Molecules: Reversal of Elicited T Cell Cytokine Profile and Partial Inhibition of Egg Granuloma Formation¹

Hector J. Hernandez^*, Arlene H. Sharpe and Miguel J. Stadecker^2,*

^* Department of Pathology, Tufts University School of Medicine, Boston, MA 02111; and Immunology Research Division, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115

	Abstract

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The granulomatous inflammation in infection with the helminth Schistosoma mansoni represents a cellular hypersensitivity reaction mediated by, and dependent upon, MHC class II-restricted CD4⁺ Th cells sensitized to parasite egg Ags. The current work examines the role and significance of the B7:CD28/CTLA-4 pathway in providing the costimulation necessary for the activation of these pathogenic T cells. In vitro T cell responses in B7-1^-/- mice, 7–8 wk postinfection, were no different from wild-type controls, but the absence of B7-2 molecules resulted in a decrease in egg Ag-induced proliferation with increased IFN- production. Both B7-1^-/- and B7-2^-/- mice exhibited intact granuloma formation. In contrast, CD4⁺ Th cells from B7-1/2 double-deficient mice displayed a dramatic loss of proliferative capacity upon stimulation with egg Ag. Most strikingly, these T cells secreted only IFN-, but not IL-4 and IL-10, a pattern entirely opposite to that displayed by wild-type controls. Despite these major differences in T cell reactivity, B7-1/2^-/- mice had only a limited reduction of granuloma size and fibrosis, without appreciable difference in cellular composition. These results show that substantial granuloma formation can occur under conditions of limited T cell expansion and restricted Th1-type cytokine production. They also support the notion that the combined effect of B7 signaling is not as critical for Th1 cell activation as it is for the development of the Th2 dominant environment characteristic of the evolving schistosome infection in H-2^b mice.

	Introduction

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Infection with the helminth Schistosoma mansoni results in hepatic and intestinal granulomatous inflammation around parasite eggs that can lead to severe hepatic fibrosis, portal hypertension, gastro-intestinal hemorrhage, and death 1, 2 . Early studies in an experimental mouse model have shown that formation of egg granulomas is strictly dependent upon T cells, as these lesions do not form in athymic mice 3 . More recently, it was demonstrated that the T cells mediating granuloma formation are egg Ag-specific CD4⁺ Th cells expressing the ß heterodimeric receptor for Ag 4, 5, 6 . CD4⁺ Th cells are divided into two functional subpopulations based on differential cytokine secretion 7 . Th1 cells secrete IL-2 and IFN- and participate in cell-mediated immune reactions, while Th2 cells, which secrete IL-4, IL-5, and IL-10, provide help for humoral immune responses. There is evidence that both subtypes participate in the immunopathological response to schistosomes. A Th2-type dominant profile usually follows an initial Th1-type response 8, 9, 10 .

CD4⁺ Th cells typically respond to exogenous Ags presented by accessory cells that express a primary signal consisting of complexed complexes of MHC class II molecules and specific Ag peptides, which engage the corresponding clonotypic TCR. However, optimal responses of CD4⁺ Th cells require a secondary signal, provided by costimulatory molecules. The B7 family of proteins, B7-1 (CD80) 11, 12 and B7-2 (CD86) 13, 14, 15 , provide the major costimulatory signal for augmenting and sustaining a T cell response via interaction with the CD28 costimulatory receptor 16, 17 . B7 costimulators also bind CTLA-4 18 , which can provide a negative signal down-regulating T cell activation 19, 20 . The dual specificity of B7 molecules for CD28 and CTLA-4 have made it challenging to elucidate the function of this key costimulatory pathway. Recent studies have suggested that in some models of T cell anergy the unresponsive state is due to B7-CTLA-4 interaction 21 rather than induced by an absence of B7 costimulation 22, 23, 24 .

The role of the B7:CD28/CTLA-4 pathway has been extensively investigated in vivo in a variety of experimental autoimmune and infectious disease systems 25 . In the schistosome infection, early expression of B7-2 molecules has been documented in hepatic egg granulomas by direct immunocytochemical analysis in situ 26 . Moreover, up-regulation of B7 molecules on granuloma macrophages in vitro, following neutralization of IL-10, resulted in enhanced stimulation of egg Ag-specific mono- and polyclonal Th cell responses 27 .

The critical dependence of granuloma formation on MHC class II Ags has been documented in vivo, as mice lacking class II expression, which do not develop CD4⁺ Th cells, altogether fail to mount immune or granulomatous responses to schistosome eggs 6 . The recent development of mice lacking B7-1 molecules 28 , B7-2 molecules, or both B7 molecules 29 has now made it possible to similarly scrutinize the role of the B7:CD28/CTLA-4 costimulatory pathway in experimental schistosomiasis. In particular, animals lacking both the B7-1 and B7-2 molecules provide a most advantageous and definitive model to study this disease under conditions of rigorous absence of known signaling through the B7:CD28/CTLA-4 pathway. Alternatively, the use of anti-B7-1 and anti-B7-2 mAbs may be associated with incomplete blockade, especially when examining a protracted immune response, because neutralizing Abs against the anti-B7 mAbs may be induced. In this paper, we report on the T cell response and immunopathology that develop during the schistosome infection in mice lacking either B7-1, B7-2, or both B7 molecules.

	Materials and Methods

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Mice, parasites, and schistosomal egg Ags (SEA)³

Mice deficient in B7-1 (B7-1^-/-), B7-2 (B7-2^-/-), or both (B7-1/2^-/-) molecules were made by specific gene targeting in embryonic stem cells, as described previously 28, 29 . The 129/SvJae (129) wild-type (WT) mice, used as controls, were bred in our breeding colony. Some mice were infected with 70 cercariae of S. mansoni, Puerto Rico strain. Cercariae were shed from infected Biomphalaria glabrata snails, provided by the Biomedical Research Institute (Rockville, MD). The SEA was obtained from the Center for Tropical Diseases, University of Massachusetts (Lowell, MA) in part subsidized by the United Nations Development Program/World Bank/World Health Organization Special Program for Research and Training in Tropical Diseases (Geneva, Switzerland).

Lymphocyte populations

Mesenteric lymph nodes were dissected from mice infected 7–8 wk previously with 70 cercariae of S. mansoni. The lymph node cells were used either intact, or purified CD4⁺ Th cells thereof were prepared by negative selection, as described previously 30 . Briefly, the cells were passed through a nylon wool column and subjected to two cycles of incubation in the presence of mAb against I-A^b, heat stable Ag, and CD8, followed by rabbit complement. Dead cells were eliminated by density gradient centrifugation.

Proliferation assay

Bulk lymph node cells were cultured at a concentration of 2.5 x 10⁵ cells/200 µl of medium in 96-microwell plastic plates in the presence of the indicated concentrations of SEA. The culture medium used in these experiments, the source of its components, and the culture conditions were identical to those described previously 30 . CD4⁺ Th cells were cultured at a concentration of 1.5 x 10⁵/well in the presence of SEA and 3 x 10⁵ irradiated (3000 rad) splenocytes, serving as APC, as indicated. Cultures proceeded for 96 h. During the last 24 h of culture, cells were pulsed with 0.5 µCi of [³H]TdR (Dupont-New England Nuclear, Wilmington, DE), and incorporation into DNA was measured by liquid scintillation spectroscopy.

Cytokine assays

Bulk lymph node cells (5 x 10⁶/ml), or 1 x 10⁶ CD4⁺ Th cells plus 4 x 10⁶/ml irradiated splenic APC, were cultured together with 20 µg/ml SEA in 48-well plastic plates for 48 h. The cytokines IFN-, IL-4, and IL-10 were measured in culture supernatants by ELISA, using the corresponding cytokine-specific capture mAbs, detection mAbs, standard cytokines, and protocols from PharMingen (San Diego, CA).

Assessment of hepatic pathology

Hepatic pathology was evaluated on 5-µm tissue sections stained with hematoxylin/eosin. Granuloma formation was assessed quantitatively by computer-assisted morphometric analysis using Image Pro Plus software (Image Processing Solutions, North Reading, MA) by observers unaware of the experimental conditions. Data are expressed in surface units. Hepatic fibrosis was assessed by measuring hydroxyproline, as described previously 31 .

	Results

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Hepatic immunopathology and in vitro immune response in schistosome-infected B7-1^-/- and B7-2^-/- mice

In a first set of experiments, we compared the outcome of the schistosome infection in mice lacking either B7-1 or B7-2 with WT controls. After 7–8 wk of infection, livers were subjected to quantitative histopathological analysis, and bulk cell populations or purified CD4⁺ Th cells from the mesenteric lymph nodes were used to assess proliferative and cytokine responses to SEA.

Examination of livers from B7-1^-/- and B7-2^-/- mice after 7 to 8-wk schistosome infections revealed egg granuloma formation comparable with that seen in WT mice. This was confirmed by computer-assisted morphometric analysis, which reflected no significant difference between the groups, as shown in Table I. The composition of the granulomas in terms of inflammatory cells was similar as well.

View larger version (18K): [in this window] [in a new window]   FIGURE 1. Mesenteric lymph node cell proliferative responses in B7-1-/-, B7-2-/-, and WT mice. Cells were obtained from 7 to 8-wk infected mice, plated at a concentration of 2.5 x 105/microwell, and cultured for 96 h in the presence of SEA. During the last 24 h of the incubation period, 0.5 µCi of [3H]TdR was added to each well. 3H incorporation into DNA was assessed by liquid scintillation spectroscopy. Points represent mean cpm ± SEM of triplicate determinations. B7-2-/- values are statistically significantly different from WT controls by the Student t test (p < 0.05). All experiments shown were repeated two to four times with comparable results. Only statistically significant differences are given.

View larger version (18K): [in this window] [in a new window]   FIGURE 2. Proliferative responses of CD4+ Th cells from B7-1-/-, B7-2-/-, and WT mice. Cells were obtained from 7 to 8-wk infected mice, purified as described in Materials and Methods, and cultured at a concentration of 1.5 x 105 together with SEA and 3 x 105 irradiated normal splenic APC from the indicated sources. Culture conditions and assessment of proliferation were identical to those described in Fig. 1. Points represent mean cpm ± SEM of triplicate determinations. B7-2-/- values are significantly different from WT controls (p < 0.005). Values for all T cell cultures in the absence of APC were <610 cpm.

View larger version (27K): [in this window] [in a new window]   FIGURE 3. Cytokine production by mesenteric lymph node cells from B7-1-/-, B7-2-/-, and WT mice. Cells were obtained from 7 to 8-wk infected mice and plated in 48-well plates at a concentration of 5 x 106/ml in the presence of 20 µg/ml of SEA. After 48 h, IFN-, IL-4, and IL-10 present in the culture supernatants were measured by ELISA. Bars represent means ± SEM of triplicate determinations. For IFN-, B7-2-/- value is significantly different from WT control (p < 0.005); for IL-4, B7-1-/- and B7-2-/- values are significantly different from WT controls (p < 0.005 and p < 0.0005, respectively); and for IL-10, B7-1-/- and B7-2-/- values are significantly different from WT controls (p < 0.05 and p < 0.005, respectively). IFN- values in the absence of SEA were <0.024 ng/ml. IL-4 and IL-10 were not detected in the absence of SEA.

View larger version (12K): [in this window] [in a new window]   FIGURE 4. Cytokine production by CD4+ Th cells from B7-1-/-, B7-2-/-, and WT mice. CD4+ Th cells were obtained from 7 to 8-wk infected mice, purified as described in Materials and Methods, and cultured at a concentration of 1 x 106 together with 20 µg/ml of SEA and 4 x 106 irradiated splenic APC from normal WT mice. Cytokines were determined as described in Fig. 3. Bars represent means ± SEM of triplicate determinations. For IFN-, B7-2-/- value is significantly different from WT control (p < 0.0005); for IL-4, B7-1-/- value is significantly different from WT control (p < 0.005); and for IL-10, B7-1-/- value is significantly different from WT control (p < 0.05). No cytokine was detected in the absence of SEA or APC.

A similar set of experiments was conducted to compare the immunopathology as well as the proliferative and cytokine T cell responses between schistosome-infected B7-1/2^-/- and control WT mice. Histological analysis of the B7-1/2^-/- livers after a 7 to 8-wk infection revealed a granulomatous reaction that was smaller and less fibrotic than that seen in WT controls (Table I). However, this reduction was marginally significant, and the granulomas were qualitatively indistinguishable in terms of cellular composition, including macrophages, eosinophils, and occasional multinucleated giant cells. Of interest was the unexpected presence in some B7-1/2^-/- livers of variable cytoplasmic vacuolization of hepatocytes associated with an interstitial infiltration of mono- and polymorphonuclear inflammatory cells. After 8 wk of infection, increasing hepatocellular damage was evident, causing the death of several animals. For this reason, it was not possible to examine the progression of egg granulomas and related T cell parameters at later time points.

The in vitro proliferative response to SEA by bulk B7-1/2^-/- lymph node cells was profoundly inhibited when compared with WT control cells (Fig. 5). Purified WT CD4⁺ Th cells were less effectively stimulated by B7-1/2^-/- splenic APC than by the homologous WT counterparts (Fig. 6), but, most strikingly, B7-1/2^-/- CD4⁺ Th cells altogether failed to respond to SEA in the presence of homologous B7-1/2^-/- splenic APC and only gave marginal responses in the presence of WT APC. These results demonstrate that splenic APC lacking B7-1 and B7-2 molecules are suboptimal in stimulating the SEA-specific WT CD4⁺ Th cells and that there is defective CD4⁺ Th cell priming to SEA in schistosome-infected mice lacking both B7-1 and B7-2 molecules.

View larger version (15K): [in this window] [in a new window]   FIGURE 5. Mesenteric lymph node cell proliferative responses in B7-1/2-/- and WT mice. Cell culture conditions and assessment of proliferation were identical to those described in Fig. 1. Points represent mean cpm ± SEM of triplicate determinations. B7-1/2-/- values are significantly different from WT controls (p < 0.0005).

View larger version (15K): [in this window] [in a new window]   FIGURE 6. Proliferative responses of CD4+ Th cells from B7-1/2-/- and WT mice. Cell culture conditions and assessment of proliferation were identical to those described in Fig. 2. Points represent mean cpm ± SEM of triplicate determinations. Values for B7-1/2-/- CD4+ Th cells are significantly different from corresponding WT controls, both with WT APC and B7-1/2-/- APC (p < 0.005). Values for all T cell cultures in the absence of APC were <600 cpm. Value for B7-1/2-/- CD4+ T cells stimulated with 20 U/ml of IL-2 in the presence of B7-1/2-/- APC was equal to 37020 cpm.

View larger version (21K): [in this window] [in a new window]   FIGURE 7. Cytokine production by mesenteric lymph node cells from B7-1/2-/- and WT mice. Cell culture conditions and cytokine assays were identical to those described in Fig. 3. Bars represent means ± SEM of triplicate determinations. B7-1/2-/- values for all cytokines are significantly different from WT controls (p < 0.005). IFN- values in the absence of SEA were <0.62 ng/ml. IL-4 and IL-10 values in the absence of SEA were <0.0013 ng/ml.

View larger version (11K): [in this window] [in a new window]   FIGURE 8. Cytokine production by CD4+ Th cells from B7-1/2-/- and WT mice. Cell culture conditions and cytokine assays were identical to those described in Fig. 4. Bars represent means ± SEM of triplicate determinations. B7-1/2-/- values for all cytokines are significantly different from WT controls (p < 0.05). IFN- values in the absence of SEA or APC were <0.06 ng/ml. Il-4 and IL-10 were not detected in the absence of SEA or APC.

	Discussion

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In contrast to the mice lacking either B7-1 or B7-2, infected mice lacking both B7 molecules displayed dramatic changes in their lymphoid cell responses to SEA in vitro, as well as significant differences in the hepatic pathology in vivo. Our results showed that in the absence of both B7 molecules, SEA-stimulated CD4⁺ Th cells are incapable of mounting proliferative responses and that, strikingly, their cytokine response is predominantly, if not entirely, of the Th1 type. These observations suggest that the combined effect of both B7-1 plus B7-2 signaling is required for the development of the Th2-dominant/Th1-poor response characteristically seen in week 7–8 of infection in H-2^b mice 8, 9, 10 .

An impaired Th2 response, as well as the development of significant hepatic immunopathology in a Th1 cytokine dominant milieu, agrees with a study of King et al. 32 , who examined the schistosome infection in CD28-deficient mice and also reported an inhibition of the Th2-associated IgG1, but not of the Th1-associated IgG2a response in these mice. However, proliferative and IFN- responses to SEA were found to be normal, and there was no demonstrable effect on hepatic egg granuloma formation associated with the natural infection. These differences may be attributable to residual signaling through the B7:CD28/CTLA-4 pathway in the CD28-deficient mouse, as recently demonstrated 33, 34 . In a related study, the same depression of Th-2 cytokines was achieved with anti-B7-2 Abs, but, in contrast to the natural infection, this treatment inhibited the formation of granulomas around lung-embolized eggs injected i.v. 35 . In our hands, treatment with anti-B7-1 and/or anti-B7-2 mAbs had no effect on hepatic egg granulomas associated with the natural infection (data not shown).

Our studies indicate that CD4⁺ Th cells, abnormally primed to SEA in the absence of B7 costimulation, proliferate poorly, but secrete IFN- when stimulated with Ag, a situation similarly described in C57BL/6 invariant chain-deficient mice, which have an impaired ability to present class II-restricted Ags and develop reduced numbers of CD4⁺ Th cells that secrete IFN- but do not proliferate normally 36 . Our findings, together with those of King et al. 32 , lend support to the notion that, taken together, the B7:CD28/CTLA-4 pathway is necessary for the development of Th2 cells 37, 38, 39, 40, 41, 42 and normal B cell function 29 . Indeed, in B7-1/2^-/--deficient mice, there is absent germinal center formation and impaired Ig isotype switching 29 . Interestingly, the schistosome infection in J_H-deficient mice, which have no B cells or Abs, shares many of the characteristics seen in the B7 knockout mice and is marked by normal granuloma formation in a Th1-dominant environment 30 .

There appear to be complementary functions of B7-1 and B7-2 in which the absence of B7-2 is most consequential, but only the combined defect seems to lead to sufficient immunological changes that alter the hepatic immunopathology. Even though somewhat reduced in size and fibrous matrix, granuloma formation in B7-1/2^-/- mice is qualitatively indistinguishable from WT controls and far greater than the scanty perioval cell aggregates observed in nude 3 , MHC class II 6 , TCR ß 5 , or Rag-1-deficient mice 5 , all of which have no CD4⁺ Th cells. If their in vitro attributes were to be similar in vivo, it appears that CD4⁺ Th from B7-1/2^-/- mice are capable of mediating substantial granuloma formation under circumstances of impaired clonal expansion and altered cytokine production. These findings suggest that relatively few SEA-specific CD4⁺ Th cells suffice to spark granuloma formation. They also imply that the B7:CD28/CTLA-4 costimulatory pathway is either not necessary or is largely compensated by another system, to provide the second signal for the observed schistosome-specific Th1-type response. It is possible that in the absence of B7 costimulation, the generated Th1 response is suboptimal and accounts for the somewhat diminished granuloma formation, although it could be argued that this additional granulomatous inflammation is normally mediated by Th2 cells.

The results in the schistosome model complement our studies using D011.10 TCR transgenic mice, in which we demonstrated that if TCR stimulation is intense enough to induce some IL-2, IFN- production will occur in the absence of B7 costimulation. We have found that B7-mediated costimulation mainly affects IL-4 and IL-2 production by naive D011.10 T cells and influences IL-2 production in activated D011.10 T cells 43 . Furthermore, when naive D011.10 TCR transgenic T cells were stimulated with APC lacking either B7-1 or B7-2 alone, we observed that B7-2 had a major influence on, but was not obligatory for, IL-4 production 44 .

Finally, the basis of the observed liver cell changes in infected B7-1/2^-/- mice is not clear. An increase in IL-12 and nitric oxide, along with IFN-, and the absence of regulatory Th2 cytokines, such as IL-4 and IL-10, may be a possible explanation, although a direct effect of egg secretions cannot be excluded. However, these changes may also be the consequence of the loss of a yet unknown function controlled by the B7:CD28/CTLA-4 pathway.

	Acknowledgments

 
We thank Drs. Yong Wang and Gerardo A. Mirkin for performing the morphometric analysis of the granulomatous lesions, Dr. Allen W. Cheever for measuring the fibrosis in the liver samples, and Diana Pierce for expert editorial assistance.

	Footnotes

 
¹ This work was supported in part by U.S. Public Health Service Grants AI 18919 (to M.J.S.) and AI 38310 (to A.H.S.), and by the United Nations Development Program/World Bank World Health Organization Special Programme for Research and Training in Tropical Diseases (to M.J.S.).

² Address correspondence and reprint requests to Dr. Miguel J. Stadecker, Department of Pathology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111.

³ Abbreviations used in this paper: SEA, schistosomal egg Ag; WT, wild type.

Received for publication August 12, 1998. Accepted for publication November 23, 1998.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Smithers, S. R., and M. J. Doenhoff. 1982. Immunology of Parasitic Diseases. S. Cohen and K. S. Warren, eds. Blackwell Scientific, Boston, p. 527.
2. Boros, D. L.. 1989. Immunopathology of Schistosoma mansoni infection. Clin. Microbiol. Rev. 2:250.[Abstract/Free Full Text]
3. Phillips, S. M., J. J. DiConza, J. A. Gold, W. A. Reid. 1977. Schistosomiasis in the congenitally athymic (nude) mouse. I. Thymic dependency of eosinophilia, granuloma formation, and host morbidity. J. Immunol. 118:594.[Abstract/Free Full Text]
4. Matthew, R. C., D. L. Boros. 1986. Anti-L3T4 antibody treatment suppresses granuloma formation, and abrogates antigen induced interleukin 2 production in Schistosoma mansoni infection. Infect. Immun. 54:820.[Abstract/Free Full Text]
5. Iacomini, J., D. E. Ricklan, M. J. Stadecker. 1995. T cells expressing the T cell receptor are not required for egg granuloma formation in schistosomiasis. Eur. J. Immunol. 25:884.[Medline]
6. Hernandez, H. J., Y. Wang, N. Tzellas, M. J. Stadecker. 1997. Expression of class II, but not class I, major histocompatibility complex molecules is required for granuloma formation in infection with Schistosoma mansoni. Eur. J. Immunol. 27:1170.[Medline]
7. Mosmann, T. R., R. L. Coffman. 1989. TH-1 and TH-2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7:145.[Medline]
8. Pearce, E. J., P. Caspar, J. M. Grzych, F. Lewis, A. Sher. 1991. Down regulation of Th1 cytokine production accompanies induction of Th2 responses by a parasite helminth, Schistosoma mansoni. J. Exp. Med. 173:159.[Abstract/Free Full Text]
9. Wynn, T. A., I. Eltoum, A. W. Cheever, A. Sher. 1993. Analysis of cytokine mRNA expression during primary granuloma formation induced by eggs of Schistosoma mansoni. J. Immunol. 151:1430.[Abstract]
10. Stadecker, M. J., H. J. Hernandez. 1998. The immune response and immunopathology in infection with Schistosoma mansoni: a key role of major egg antigen Sm-p40. Parasite Immunol. 20:217.[Medline]
11. Freeman, G. J., A. S. Freedman, J. M. Segil, G. Lee, J. F. Whitman, L. M. Nadler. 1989. B7, a new member of the Ig superfamily with unique expression on activated and neoplastic B cells. J. Immunol. 143:2714.[Abstract]
12. Freeman, G. J., G. S. Gray, C. D. Gimmi, D. B. Lombard, L. J. Zhou, M. White, J. D. Fingeroth, J. G. Gribben, L. M. Nadler. 1991. Structure, expression, and T cell costimulatory activity of the murine homologue of the human B lymphocyte activation antigen B7. J. Exp. Med. 174:625.[Abstract/Free Full Text]
13. Freeman, G. J., F. Borriello, R. J. Hodes, H. Reiser, J. J. Gribben, J. W. Ng, J. Kim, J. M. Goldberg, K. G. L. Hathcock, L. A. Lombard, et al 1993. Murine B7-2, an alternative CTLA-4 counter-receptor that costimulates T cell proliferation and interleukin-2 production. J. Exp. Med. 178:2185.[Abstract/Free Full Text]
14. Freeman, G. J., J. G. Gribben, V. A. Boussiotis, J. W. Ng, V. Restivo, L. Lombard. G. S. Gray, L. M. Nadler. 1993. Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation. Science 262:909.[Abstract/Free Full Text]
15. Azuma, M., D. Ito, H. Yagita, K. Okumura, J. H. Phillips, L. L. Lanier, C. Somoza. 1993. B70 antigen is a second ligand for CTLA-4 and CD28. Nature 366:76.[Medline]
16. Linsley, P. S., E. A. Clark, J. A. Ledbetter. 1990. T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. Proc. Natl. Acad. Sci. USA 87:5031.[Abstract/Free Full Text]
17. June, C. H., J. A. Bluestone, L. M. Nadler, C. B. Thompson. 1994. The B7 and CD28 receptor families. Immunol. Today 15:321.[Medline]
18. Harper, K., C. Balzano, E. Rouvier, M. G. Mattei, M. F. Luciani, P. Goldstein. 1991. CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location. J. Immunol. 147:1037.[Abstract]
19. Waterhouse, P., J. M. Penninger, E. Timms, A. Wakeham, K. P. Lee, C. B. Thompson, H. Griesser, T. W. Mak. 1995. Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 270:985.[Abstract/Free Full Text]
20. Tivol, E. A., F. Borriello, A. N. Schweitzer, W. P. Lynch, J. A. Bluestone, A. H. Sharpe. 1995. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541.[Medline]
21. Perez, V. L., L. Van Parijs, A. Biuckians, X. X. Zheng, T. B. Strom, A. K. Abbas. 1997. Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. Immunity 6:411.[Medline]
22. Harding, F. A., J. G. McArthur, J. A. Gross, D. H. Raulet, J. P. Allison. 1992. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T cell clones. Nature 356:607.[Medline]
23. Gimmi, C. D., G. J. Freeman, J. G. Gribben, G. Gray, L. M. Nadler. 1993. Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation. Proc. Natl. Acad. Sci. USA 90:6486.
24. Chen, C., N. Nabavi. 1994. In vitro induction of T cell anergy by blocking B7 and early T cell costimulatory molecule ETC-1/B7-2. Immunity 1:147.[Medline]
25. Reiser, H., M. J. Stadecker. 1996. Costimulatory B7 molecules in the pathogenesis of infectious and autoimmune diseases. N. Engl. J. Med. 335:1369.[Free Full Text]
26. Rathore, A., C. Sacristan, D. E. Ricklan, P. O. Flores Villanueva, M. J. Stadecker. 1996. In situ analysis of B7-2 costimulatory, major histocompatibility complex class II, and adhesion molecule expression in schistosomal egg granulomas. Am. J. Pathol. 149:187.[Abstract]
27. Flores Villanueva, P. O., H. Reiser, M. J. Stadecker. 1994. Regulation of Th cell responses in experimental murine schistosomiasis by IL-10: effect on expression of B7 and B7-2 costimulatory molecules by macrophages. J. Immunol. 153:5190.[Abstract]
28. Freeman, G. J., F. Borriello, R. J. Hodes, H. Reiser, K. S. Hathcock, G. Laszlo, A. J. McKnight, J. L. D. Kim, D. B. Lombard, G. S. Gray, L. M. Nadler, A. H. Sharpe. 1993. Uncovering of functional alternative CTLA-4 counter-receptor in B7-deficient mice. Science 262:907.[Abstract/Free Full Text]
29. Borriello, F., M. P. Sethna, S. D. Boyd, A. N. Schweitzer, E. A. Tivol, D. Jacoby, T. B. Strom, E. M. Simpson, G. J. Freeman, A. H. Sharpe. 1997. B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation. Immunity 6:303.[Medline]
30. Hernandez, H. J., Y. Wang, M. J. Stadecker. 1997. In infection with Schistosoma mansoni, B cells are required for Th2 cell responses but not for granuloma formation. J. Immunol. 158:4832.[Abstract]
31. Berman, I., R. Loxley. 1963. Two improved and simplified methods for the spectrophotometric determination of hydroxyproline. Anal. Biochem. 35:1961.
32. King, C. L., J. Xianli, C. H. June, R. Abe, K. P. Lee. 1996. CD28-deficient mice generate an impaired Th2 response to Schistosoma mansoni infection. Eur. J. Immunol. 26:2448.[Medline]
33. Fallarino, F., P. E. Fields, T. F. Gajewski. 1998. B7-1 engagement of cytotoxic T lymphocyte antigen 4 inhibits T cell activation in the absence of CD28. J. Exp. Med. 188:205.[Abstract/Free Full Text]
34. Lin, H., J. C. Rathmell, G. S. Gray, C. B. Thompson, J. M. Leiden, M. L. Alegre. 1998. Cytotoxic T lymphocyte antigen 4 (CTLA4) blockade accelerates the acute rejection of cardiac allografts in CD28-deficient mice: CTLA4 can function independently of CD28. J. Exp. Med. 188:199.[Abstract/Free Full Text]
35. Subramanian, G., J. W. Kazura, E. Pearlman, X. Jia, I. Malhotra, C. L. King.. 1997. B7-2 requirement for helminth-induced granuloma formation and CD4 type 2 Th cell cytokine expression. J. Immunol. 158:5914.[Abstract]
36. Brown, D. R., K. Swier, N. H. Moskowitz, M. F. Naujokas, R. M. Locksley, S. L. Reiner. 1997. T helper subset differentiation in the absence of invariant chain. J. Exp. Med. 185:31.[Abstract/Free Full Text]
37. Freeman, G. J., V. A. Boussiotis, A. Anumanthan, G. M. Bernstein, X. Y. Ke, P. D. Rennert, G. S. Gray, J. G. Gribben, L. M. Nadler. 1995. B7-1 and B7-2 do not deliver identical costimulatory signals, since B7-2 but not B7-1 preferentially costimulates the initial production of IL-4. Immunity 2:523.[Medline]
38. Shahinian, A., K. Pfeffer, K. P. Lee, T. M. Kundig, K. Kishihara, A. Wakeham, K. Kawai, P. S. Ohashi, C. B. Thompson, T. W. Mak. 1993. Differential T cell costimulatory requirements in CD28-deficient mice. Science 261:609.[Abstract/Free Full Text]
39. Kuchroo, V. K., M. P. Das, J. A. Brown, A. M. Ranger, S. S. Zamwil, R. A. Sobel, H. L. Weiner, N. Nabavi, L. H. Glimcher. 1995. B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell 80:707.[Medline]
40. Corry, D. B., S. L. Reiner, P. S. Linsley, R. M. Locksley. 1994. Differential effects of blockade of CD28:B7 on the development of Th1 or Th2 effector cells in experimental leishmaniasis. J. Immunol. 153:4142.[Abstract]
41. Nakajima, A., N. Watanabe, S. Yoshino, H. Yagita, K. Okumura, M. Azuma. 1997. Requirement of CD28-CD86 co-stimulation in the interaction between antigen-primed T helper type 2 and B cells. Int. Immunol. 9:637.[Abstract/Free Full Text]
42. Brown, J. A., R. G. Titus, N. Nabavi, L. H. Glimcher. 1996. Blockade of CD86 ameliorates Leishmania major infection by down-regulating the Th2 response. J. Infect. Dis. 174:1303.[Medline]
43. Schweitzer, A. N., A. H. Sharpe. 1998. Studies using antigen-presenting cells lacking expression of both B7-1 (CD80) and B7-2 (CD86) show distinct requirements for B7 molecules during priming versus restimulation and Th-2 but not Th-1 cytokine production. J. Immunol. 161:2762.[Abstract/Free Full Text]
44. Schweitzer, A. N., F. Borriello, R. C. Wong, A. K. Abbas, A. H. Sharpe. 1997. Role of costimulators in T cell differentiation: studies using antigen-presenting cells lacking expression of CD80 or CD86. J. Immunol. 158:2713.[Abstract]

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