Selective CD28 antagonist blunts memory immune responses and promotes long-term control of skin inflammation in nonhuman primates

Nicolas Poirier, Melanie Chevalier, Caroline Mary, Jeremy Hervouet, David Minault, Paul Baker, Simon Ville, Stephanie Le Bas-Bernardet, Nahzli Dilek, Lyssia Belarif, Elisabeth Cassagnau, Linda Scobie, Gilles Blancho, Bernard Vanhove

Research output: Contribution to journalArticle

Abstract

Novel therapies that specifically target activation and expansion of pathogenic immune cell subsets responsible for autoimmune attacks are needed to confer long-term remission. Pathogenic cells in autoimmunity include memory T lymphocytes that are long-lived and present rapid recall effector functions with reduced activation requirements. Whereas the CD28 costimulation pathway predominantly controls priming of naive T cells and hence generation of adaptive memory cells, the roles of CD28 costimulation on established memory T lymphocytes and the recall of memory responses remain controversial. In contrast to CD80/86 antagonists (CTLA4-Ig), selective CD28 antagonists blunt T cell costimulation while sparing CTLA-4 and PD-L1–dependent coinhibitory signals. Using a new selective CD28 antagonist, we showed that Ag-specific reactivation of human memory T lymphocytes was prevented. Selective CD28 blockade controlled both cellular and humoral memory recall in nonhuman primates and induced long-term Ag-specific unresponsiveness in a memory T cell–mediated inflammatory skin model. No modification of memory T lymphocytes subsets or numbers was observed in the periphery, and importantly no significant reactivation of quiescent viruses was noticed. These findings indicate that pathogenic memory T cell responses are controlled by both CD28 and CTLA-4/PD-L1 cosignals in vivo and that selectively targeting CD28 would help to promote remission of autoimmune diseases and control chronic inflammation.
Original languageEnglish
Pages (from-to)274-283
Number of pages10
JournalJournal of Immunology
Volume196
Issue number1
DOIs
Publication statusPublished - 1 Jan 2016

Keywords

  • pathogenic immune cell subsets
  • autoimmune attacks
  • pathogenic cells
  • CD28 costimulation
  • skin inflammation
  • T lymphocytes
  • T cells
  • nonhuman primates

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    Poirier, N., Chevalier, M., Mary, C., Hervouet, J., Minault, D., Baker, P., Ville, S., Le Bas-Bernardet, S., Dilek, N., Belarif, L., Cassagnau, E., Scobie, L., Blancho, G., & Vanhove, B. (2016). Selective CD28 antagonist blunts memory immune responses and promotes long-term control of skin inflammation in nonhuman primates. Journal of Immunology, 196(1), 274-283. https://doi.org/10.4049/jimmunol.1501810