Infection-induced resistance to experimental cerebral malaria is dependent upon secreted antibody-mediated inhibition of pathogenic CD8+ T cell responses
Shaw, Tovah N., Inkson, Colette A., Villegas-Mendez, Ana, Pattinson, David J., Strangward, Patrick, Else, Kathryn J., Draper, Simon J., zeef, Leo A.H., and Couper, Kevin N. (2019) Infection-induced resistance to experimental cerebral malaria is dependent upon secreted antibody-mediated inhibition of pathogenic CD8+ T cell responses. Frontiers in Immunology, 10. 248.
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Abstract
Cerebral malaria (CM) is one of the most severe complications of Plasmodium falciparum infection. There is evidence that repeated parasite exposure promotes resistance against CM. However, the immunological basis of this infection-induced resistance remains poorly understood. Here, utilizing the Plasmodium berghei ANKA (PbA) model of experimental cerebral malaria (ECM), we show that three rounds of infection and drug-cure protects against the development of ECM during a subsequent fourth (4X) infection. Exposure-induced resistance was associated with specific suppression of CD8+ T cell activation and CTL-related pathways, which corresponded with the development of heterogeneous atypical B cell populations as well as the gradual infection-induced generation and maintenance of high levels of anti-parasite IgG. Mechanistically, transfer of high-titer anti-parasite IgG did not protect 1X infected mice against ECM and depletion of atypical and regulatory B cells during 4X infection failed to abrogate infection-induced resistance to ECM. However, IgMi mice that were unable to produce secreted antibody, or undergo class switching, during the repeated rounds of infection failed to develop resistance against ECM. The failure of infection-induced protection in IgMi mice was associated with impaired development of atypical B cell populations and the inability to suppress pathogenic CD8+ T cell responses. Our results, therefore, suggest the importance of anti-parasite antibody responses, gradually acquired, and maintained through repeated Plasmodium infections, for modulating the B cell compartment and eventually suppressing memory CD8+ T cell reactivation to establish infection-induced resistance to ECM.
| Item ID: | 60632 |
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| Item Type: | Article (Research - C1) |
| ISSN: | 1664-3224 |
| Copyright Information: | Copyright © 2019 Shaw, Inkson, Villegas-Mendez, Pattinson, Strangward, Else, Draper, Zeef and Couper. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and thecopyright owner(s) are credited and that the original publication in this journalis cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| Funders: | International Union of Immunological Societies (IUIS) |
| Date Deposited: | 29 Oct 2019 02:15 |
| FoR Codes: | 32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320405 Humoural immunology and immunochemistry @ 100% |
| SEO Codes: | 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 100% |
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