The B7 family member B7-H3 preferentially down-regulates T helper type 1–mediated immune responses

Suh, Woong‐Kyung; Gajewska, Beata; Okada, Hitoshi; Gronski, Matthew A; Bertram, Edward M.; Dawicki, Wojciech; Duncan, Gordon S.; Bukczynski, Jacob; Plyte, Suzanne; Elia, Andrew; Wakeham, Andrew; Itié, Annick; Chung, Stephen W.; Costa, Joan da; Arya, Sudha; Horan, Tom; Campbell, Pauline; Gaida, Kevin; Ohashi, Pamela S.; Watts, Tania H.; Yoshinaga, Steven K.; Bray, Mark R.; Jordana, Manel; Mak, Tak W.

doi:10.1038/ni967

Cited by 471 publications

(475 citation statements)

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“…Lastly, while our data demonstrating a positive regulatory pathway for B7-H3 are consistent with other work [9,12,14], they differ from reports showing negative regulatory functions of mB7-H3 [15,16]. The reasons for this are unclear, though certainly different targeting strategies, assays, and models were employed.…”

Section: Discussionsupporting

confidence: 83%

“…In our own studies involving human and mouse T cells activated by plate-bound CD3 mAb with or without plate-bound B7-H3.Ig similarly to that described by Suh et al [15], impairment of T cell activation was indeed observed on occasion, but we determined that the inhibition was an artifact due to B7-H3.Ig blocking the anti-CD3 and reducing the stimulation available to the T cells; no such effect was seen using soluble anti-CD3 mAb and plate-bound B7-H3.Ig, or plate-bound CD3 mAb and soluble B7-H3.Ig.…”

Section: Discussionmentioning

confidence: 74%

“…The reasons for this are unclear, though certainly different targeting strategies, assays, and models were employed. For example, generation of the previously described B7-H3 -/-mouse [15] involved deletion of just the second Ig domain of B7-H3, and the success of targeting was evaluated using a rabbit polyclonal antibody; it is possible, albeit unlikely, that partial expression of the first Ig domain of B7-H3 has persisted with unexpected effects on host immune responses. Our own knockout mouse involved deletion of exons 2 and 3, and recently we obtained from Eli Lilly a third B7-H3 -/-mouse line with deletion of exon 1 and part of exon 2, use of which in our hands also showed decreased T cell proliferative responses (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…Subsequent studies of intratumor expression of B7-H3 from the Chen laboratory [14] (where B7-H3 was first described) showed a costimulatory effect of B7-H3 and enhanced tumor immunity in vivo and in vitro in a mouse model. However, recently Suh et al [15] published the first characterization of a B7-H3 -/-mouse whose use for in vitro and in vivo studies suggested, surprisingly, that B7-H3 has a suppressive effect on mouse T cell activation and functions, leading the authors to suggest that B7-H3 is involved in feedback inhibition of Th1-mediated immune responses. Similarly, employing an anti-B7-H3 mAb, Prasad et al [16] showed a negative regulatory effect of B7-H3 on T cells.…”

Section: Introductionmentioning

confidence: 99%

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B7‐H3 promotes acute and chronic allograft rejection

et al. 2005

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The B7 homolog B7-H3 is important for the regulation of immune responses though its functions in vivo are controversial. We report the first clinical and experimental data concerning expression and function of B7-H3 in alloresponses. Immunohistological and molecular analyses showed B7-H3 expression by cells mediating rejection of human and mouse allografts. To analyze the significance of B7-H3 in rejecting allografts, we generated B7-H3 -/-mice and showed that targeting of B7-H3 was synergistic with other forms of immune modulation; e.g. a regimen of rapamycin gave 12-14 days of survival in wild-type controls but led to permanent cardiac and islet allograft survival in B7-H3 -/-mice. Cardiac allografts in treated B7-H3 -/-mice showed markedly decreased production of key cytokine, chemokine and chemokine receptor mRNA transcripts as compared to wild-type controls. The incidence of chronic rejection in two different cardiac allograft models was also inhibited in B7-H3 -/-as compared to wild-type recipients. Lastly, in addition to the expected antigen-presenting cell expression of B7-H3, CD4 and CD8 T cells showed B7-H3 induction upon cell activation, and both dendritic cell-and T cell-expressed B7-H3 each enhanced T cell proliferation in vitro and in vivo. We conclude that B7-H3 promotes T cell-mediated immune responses and the development of acute and chronic allograft rejection.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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B7‐H3 promotes acute and chronic allograft rejection

et al. 2005

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“…Murine B7-H3 was also described as a two-Ig molecule, and using a B7-H3-Ig fusion protein, evidence for a counter-receptor that is induced on T cells upon activation was found (7). Analyzing B7-H3-deficient mice, one group reported enhanced Th1-type responses in vivo, whereas another group found enhanced antitumor immunity in mice challenged with EL-4 cells transfected to express B7-H3 (8,9).…”

Section: Molecular Characterization Of Human 4ig-b7-h3 a Member Of Tmentioning

confidence: 99%

Molecular Characterization of Human 4Ig-B7-H3, a Member of the B7 Family with Four Ig-Like Domains

Schmitz

Majdic

Derdak

et al. 2004

The Journal of Immunology

231

245

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In an effort to characterize molecules with immunoregulatory potential, we raised mAbs to human dendritic cells. We selected an Ab that recognizes a molecule that is induced on monocytes differentiated in vitro toward dendritic cells. Retroviral expression cloning identified this molecule as B7-H3, a member of the B7 family described recently. In contrast to an earlier report, in which B7-H3 was described as a molecule consisting of two Ig-like domains, our cDNA encoded a type I membrane protein with four Ig-like domains, and the molecule identified by us was therefore named 4Ig-B7-H3. mRNA analysis as well as Western blotting experiments performed by us did not reveal evidence for a small B7-H3. B7-H3 is not expressed on peripheral blood lymphocytes, monocytes, or granulocytes. Upon in vitro stimulation, the expression of B7-H3 is induced on T cells, B cells, and NK cells. A number of different approaches were used to investigate the function of human B7-H3. In contrast to an earlier report, our data do not support a costimulatory role of B7-H3 in anti-CD3-mediated activation of the TCR-complex resulting in T cell proliferation and IFN-γ production.

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Multiplexed digital spatial profiling of invasive breast tumors from Black and White women

et al. 2021

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The NanoString GeoMx Digital Spatial Profiling (DSP) is a new multiplexed platform that quantifies the abundance of tumor-and immune-related proteins in a spatially resolved manner. We performed DSP for the simultaneous assessment of 52 analytes within spatially resolved tissue compartments defined by pancytokeratin expression. We compared protein targets between 94 African American/Black and 65 European American/White cases, tumor and stromal tissue compartments, estrogen receptor alpha (ER)-positive and ER-negative cases, and explored potential biomarkers of survival. Of 33 analytes with robust signal for analysis, results were highly replicable. For a subset of markers, correlative analyses between DSP analytes and traditional immunohistochemistry (IHC) scores revealed moderate to very strong associations between the two platforms. Similarly, DSP analytes and gene expression scores were concordant for 21 of 25 markers with overlap between the two datasets. Several analytes varied by ER status, and across the 25 immune markers surveyed, 14 had a significant inverse association with ER expression. B7 homolog 3 (B7-H3; encoded by CD276) was the only analyte to show a significant difference by race, being lower in both the tumor and stromal compartments in Black women. DSP markers that were associated with survival included CD8, CD25, CD56, CD127, EpCAM, ER, Ki-67, and STING. We conclude that DSP is an efficient tool for screening tumorand immune-related markers in a simultaneous fashion and yields results that are concordant with established immune profiling assays. DSP immune analytes were inversely associated with ER expression, in agreement with a substantial body of previous work that documents higher immune infiltration in ERnegative breast cancers. This technology revealed that scores of the B7-H3 protein were significantly lower in breast cancers from Black women compared with White women, an intriguing finding that requires replication in independent and racially diverse female populations.

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The B7 family member B7-H3 preferentially down-regulates T helper type 1–mediated immune responses

Cited by 471 publications

References 46 publications

B7‐H3 promotes acute and chronic allograft rejection

B7‐H3 promotes acute and chronic allograft rejection

Molecular Characterization of Human 4Ig-B7-H3, a Member of the B7 Family with Four Ig-Like Domains

Multiplexed digital spatial profiling of invasive breast tumors from Black and White women

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