Journal
JOURNAL OF IMMUNOLOGY
Volume 196, Issue 1, Pages 274-283Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1501810
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Funding
- European Union [EC-GA 281493]
- Progreffe Foundation (France)
- Centaure Foundation (France)
- Institut Hospitalo-Universitaire-Centre Europeen des Sciences de la Transplantation et d'Immunotherapie project - Metropole
- Pays de la Loire Region
- Chief Scientist Office [ETM/32] Funding Source: researchfish
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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 CD80186 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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