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

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Primates
Inflammation
T-Lymphocytes
Skin
Lymphocyte Count
T-Lymphocyte Subsets
Autoimmunity
Autoimmune Diseases
Viruses

Keywords

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

Cite this

Poirier, Nicolas ; Chevalier, Melanie ; Mary, Caroline ; Hervouet, Jeremy ; Minault, David ; Baker, Paul ; Ville, Simon ; Le Bas-Bernardet, Stephanie ; Dilek, Nahzli ; Belarif, Lyssia ; Cassagnau, Elisabeth ; Scobie, Linda ; Blancho, Gilles ; Vanhove, Bernard. / Selective CD28 antagonist blunts memory immune responses and promotes long-term control of skin inflammation in nonhuman primates. In: Journal of Immunology. 2016 ; Vol. 196, No. 1. pp. 274-283.
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title = "Selective CD28 antagonist blunts memory immune responses and promotes long-term control of skin inflammation in nonhuman primates",
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.",
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author = "Nicolas Poirier and Melanie Chevalier and Caroline Mary and Jeremy Hervouet and David Minault and Paul Baker and Simon Ville and {Le Bas-Bernardet}, Stephanie and Nahzli Dilek and Lyssia Belarif and Elisabeth Cassagnau and Linda Scobie and Gilles Blancho and Bernard Vanhove",
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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, vol. 196, no. 1, pp. 274-283. https://doi.org/10.4049/jimmunol.1501810

Selective CD28 antagonist blunts memory immune responses and promotes long-term control of skin inflammation in nonhuman primates. / Poirier, Nicolas; Chevalier, Melanie; Mary, Caroline; Hervouet, Jeremy; Minault, David; Baker, Paul; Ville, Simon; Le Bas-Bernardet, Stephanie; Dilek, Nahzli; Belarif, Lyssia; Cassagnau, Elisabeth; Scobie, Linda; Blancho, Gilles; Vanhove, Bernard.

In: Journal of Immunology, Vol. 196, No. 1, 01.01.2016, p. 274-283.

Research output: Contribution to journalArticle

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T1 - Selective CD28 antagonist blunts memory immune responses and promotes long-term control of skin inflammation in nonhuman primates

AU - Poirier, Nicolas

AU - Chevalier, Melanie

AU - Mary, Caroline

AU - Hervouet, Jeremy

AU - Minault, David

AU - Baker, Paul

AU - Ville, Simon

AU - Le Bas-Bernardet, Stephanie

AU - Dilek, Nahzli

AU - Belarif, Lyssia

AU - Cassagnau, Elisabeth

AU - Scobie, Linda

AU - Blancho, Gilles

AU - Vanhove, Bernard

N1 - Accepted before 1-4-16 (online Nov 15)

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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.

AB - 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.

KW - pathogenic immune cell subsets

KW - autoimmune attacks

KW - pathogenic cells

KW - CD28 costimulation

KW - skin inflammation

KW - T lymphocytes

KW - T cells

KW - nonhuman primates

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