Functional analysis of the adhesion receptor CD155 and its ligands
Zusammenfassung der Projektergebnisse
In this project, we planned to elucidate the functions of the cellular receptor for poliovirus, CD155, and its ligands. Of central importance for our research was the generation of suitable tools, first of all the establishment of a CD155 knock-out mouse but also of a panel of monoclonal antibodies that served not only to recognize expression patterns of CD155 and its ligands but also proofed to be helpful in functional studies. We were able to identify several immunologically relevant phenotypes caused by absence of CD155 and together with the wealth of publications by other groups these insights firmly installed the CD155/ligand-network as an important modulator of innate and adaptive immunity. We could show that absence of CD155 caused a defect in the humoral immune response to orally applied antigen. This pointed to a non-redundant role of CD155 in mounting adaptive immunity in the gut-associated lymphoid tissue. The kind of defect clearly indicated that not the primary response is affected but rather the secondary, germinal center based response that also promotes immunoglobulin class switch. Among the secondary lymphoid organs, Peyer’s Patches lining the small intestine are exceptional because they constantly maintain germinal center reactions in conventionally reared mice. Therefore, it was interesting to note that Peyer’s Patches deficient for CD155 or CD226 harbor significantly less follicular helper T cells, the main component driving a germinal center reaction. We currently investigate this in more detail as part of a new research project. Furthermore, we found that CD155 and CD226 are involved in the differentiation of iNKT cells in thymus. As a consequence of a shifted iNKT subtype composition in this organ, less IL-4 producing iNKT cells are present in thymus of CD155 and CD226 deficient mice. This triggers another phenotype in these mice: a substantially reduced capacity to generate memory-like CD8 T cells. We showed that these cells are released from thymus into periphery by a slow rate that also is controlled by an ongoing CD155/CD226-interaction. The consequences of a disturbed iNKT cell differentiation and memory-like CD8 T cell generation in thymus most likely will also affect the corresponding cell populations in peripheral organs and the functions connected to them. In this context, we characterized iNKT subpopulations in great detail filling a gap in our knowledge regarding this highly specialized cell type. We also provided evidence that the CD155/ligand-system is of primordial importance in graft-versus-host-disease. How exactly the CD155 driven network modulates the severity of disease remains to be deciphered but this is of great interest due to its importance for potential therapeutic applications. In other sub-projects we focused on the CD155 ligands CD96 and CD226. We were the first to characterize human and mouse CD96 biochemically including a detailed study of its binding modality to CD155 in both species. These results also point to the limitations when concluding by analogy from functions in mouse to those in human because in case of CD96 some species specific peculiarities might exist. Furthermore, we found that the CD226 levels on NK and T cells can be manipulated by CD155 present on distinct cells contacting them in the course of immune surveillance and observed that CD226 influences the capacity of NK cells to eliminate immature dendritic cells. Taken together, our knowledge regarding the CD155/ligand-system grew tremendously in the last decade and despite of the many unanswered questions, a clear picture emerged. Although CD155 and its ligands belong to those genes that evolve rapidly, almost all CD155-based interactions were conserved between man and mouse. This emphasizes the biological importance of the CD155/ligandnetwork. The distinct interaction pattern of CD155 with its ligands in trans determine its function(s) in different branches of life science. Therefore, our focus on immunology gave rise to a “natural selection” of molecules that were in the center of our research interest apart from CD155 itself: CD96, CD226 and TIIGT. Despite of this helpful conceptual framework, it is important to mention that it disregards the importance of CD155 itself as a signaling unit as well as its interaction partners in cis such as the integrin alpha(v)beta(3), CD44 or Tctex-1 that might modulate the functions of CD155 also in immunologically relevant processes. Therefore, future research should include these aspects.
Projektbezogene Publikationen (Auswahl)
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(2007). The adhesion receptor CD155 determines the magnitude of humoral immune responses against orally ingested antigens. Eur J Immunol 37, 2214-2225
Maier, M. K., Seth, S., Czeloth, N., Qiu, Q., Ravens, I., Kremmer, E., Ebel, M., Muller, W., Pabst, O., Forster, R., and Bernhardt, G.
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(2007). The murine pan T cell marker CD96 is an adhesion receptor for CD155 and nectin-1. Biochem Biophys Res Commun 364, 959-965
Seth, S., Maier, M. K., Qiu, Q., Ravens, I., Kremmer, E., Forster, R., and Bernhardt, G.
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(2009). Abundance of follicular helper T cells in Peyer's patches is modulated by CD155. Eur J Immunol 39, 3160-3170
Seth, S., Ravens, I., Kremmer, E., Maier, M. K., Hadis, U., Hardtke, S., Forster, R., and Bernhardt, G.
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(2009). CD96 Interaction with CD155 via Its First Ig-like Domain Is Modulated by Alternative Splicing or Mutations in Distal Ig-like Domains. J Biol Chem 284, 2235-2244
Meyer, D., Seth, S., Albrecht, J., Maier, M. K., Pasquier, L., Ravens, I., Dreyer, L., Burger, R., Gramatzki, M., Schwinzer, R., Kremmer, E., Foerster, R., and Bernhardt, G.
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(2009). Heterogeneous expression of the adhesion receptor CD226 on murine NK and T cells and its function in NK-mediated killing of immature dendritic cells. J Leukoc Biol 86, 91-101
Seth, S., Georgoudaki, A. M., Chambers, B. J., Qiu, Q., Kremmer, E., Maier, M. K., Czeloth, N., Ravens, I., Foerster, R., and Bernhardt, G.
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(2010). CD155 is involved in negative selection and is required to retain terminally maturing CD8 T cells in thymus. J Immunol 184, 1681-1689
Qiu, Q., Ravens, I., Seth, S., Rathinasamy, A., Maier, M. K., Davalos-Misslitz, A., Forster, R., and Bernhardt, G.
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(2011). Absence of CD155 aggravates acute graft-versus-host disease. Proc Natl Acad Sci USA 108, E32-33; author reply E34
Seth, S., Ravens, I., Lee, C. W., Glage, S., Bleich, A., Forster, R., Bernhardt, G., and Koenecke, C.
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(2011). Intranodal Interaction with Dendritic Cells Dynamically Regulates Surface Expression of the Co-stimulatory Receptor CD226 Protein on Murine T Cells. J Biol Chem 286, 39153-39163
Seth, S., Qiu, Q., Danisch, S., Maier, M. K., Braun, A., Ravens, I., Czeloth, N., Hyde, R., Dittrich-Breiholz, O., Forster, R., and Bernhardt, G.
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(2013). CD226 interaction with CD155 impacts on retention and negative selection of CD8 positive thymocytes as well as T cell differentiation to follicular helper cells in Peyer's Patches. Immunobiology 218, 152-158
Danisch, S., Qiu, Q., Seth, S., Ravens, I., Dorsch, M., Shibuya, A., Shibuya, K., Forster, R., and Bernhardt, G.
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(2014). To the editor: TIGIT versus CD226: hegemony or coexistence? Eur J Immunol 44, 307-308
Georgiev, H., Danisch, S., Chambers, B. J., Shibuya, A., Forster, R., and Bernhardt, G.
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(2016). CD155/CD226-interaction impacts on the generation of innate CD8(+) thymocytes by regulating iNKT-cell differentiation. Eur J Immunol 46, 993-1003
Georgiev, H., Ravens, I., Shibuya, A., Forster, R., and Bernhardt, G.
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(2016). Distinct gene expression patterns correlate with developmental and functional traits of iNKT subsets. Nat Commun 7, 13116
Georgiev, H., Ravens, I., Benarafa, C., Forster, R., and Bernhardt, G.
