Suppression of CD4+ Effector Responses by Naturally Occurring CD4+ CD25+ Foxp3+ Regulatory T Cells Contributes to Experimental Cerebral Malaria.

Anne-Laurence Blanc (1, 2, 3) , Tarun Keswani (2) , Olivier Gorgette (4) , Antonio Bandeira (5) , Bernard Malissen (6) , Pierre-André Cazenave (1, 2, 3, 7) , Sylviane Pied (2, 3)

1 UPMC - Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie
2 Institut Pasteur de Lille
3 IP - Institut Pasteur [Paris]
4 Immunologie moléculaire des parasites
5 Biologie des Populations Lymphocytaires
6 CIML - Centre d'Immunologie de Marseille - Luminy
7 I3 - Immunologie - Immunopathologie - Immunothérapie

The role of naturally occurring CD4(+) CD25(+) Foxp3(+) regulatory T cells (nTreg) in the pathogenesis of cerebral malaria (CM), which involves both pathogenic T cell responses and parasite sequestration in the brain, is still unclear. To assess the contribution and dynamics of nTreg during the neuropathogenesis, we unbalanced the ratio between nTreg and naive CD4(+) T cells in an attenuated model of Plasmodium berghei ANKA-induced experimental CM (ECM) by using a selective cell enrichment strategy. We found that nTreg adoptive transfer accelerated the onset and increased the severity of CM in syngeneic C57BL/6 (B6) P. berghei ANKA-infected mice without affecting the level of parasitemia. In contrast, naive CD4(+) T cell enrichment prevented CM and promoted parasite clearance. Furthermore, early during the infection nTreg expanded in the spleen but did not efficiently migrate to the site of neuroinflammation, suggesting that nTreg exert their pathogenic action early in the spleen by suppressing the protective naive CD4(+) T cell response to P. berghei ANKA infection in vivo in both CM-susceptible (B6) and CM-resistant (B6-CD4(-/-)) mice. However, their sole transfer was not sufficient to restore CM susceptibility in two CM-resistant congenic strains tested. Altogether, these results demonstrate that nTreg are activated and functional during P. berghei ANKA infection and that they contribute to the pathogenesis of CM. They further suggest that nTreg may represent an early target for the modulation of the immune response to malaria.

Domaines: Immunologie

Anne-Laurence Blanc, Tarun Keswani, Olivier Gorgette, Antonio Bandeira, Bernard Malissen, et al.. Suppression of CD4+ Effector Responses by Naturally Occurring CD4+ CD25+ Foxp3+ Regulatory T Cells Contributes to Experimental Cerebral Malaria.. Infection and Immunity, 2015, 84 (1), pp.329-38. ⟨10.1128/IAI.00717-15⟩. ⟨pasteur-01491666⟩