Extrafollicular CD4 T cell-derived IL-10 functions rapidly and transiently to support anti-Plasmodium humoral immunity
Creators
- 1. University of Iowa
- 2. University of Chicago
- 3. Blood Center of Wisconsin
- 4. University of Melbourne
Description
Immunity against malaria depends on germinal center (GC)-derived antibody responses that are orchestrated by T follicular helper (TFH) cells. Emerging data show that the regulatory cytokine IL-10 plays an essential role in promoting GC B cell responses during both experimental malaria and virus infections. Here we investigated the cellular source and temporal role of IL-10, and whether IL-10 additionally signals to CD4 T-cells to support anti-Plasmodium humoral immunity. Distinct from reports of virus infection, we found that IL-10 was expressed by conventional, Foxp3-negative effector CD4 T cells and functioned in a B cell-intrinsic manner only during the first 96 hours of Plasmodium infection to support humoral immunity. The critical functions of IL-10 manifested only before the orchestration of GC responses and were primarily localized outside of B cell follicles. Mechanistically, our studies showed that the rapid and transient provision of IL-10 promoted B cell expression of anti-apoptotic factors, MHC class II, CD83, and cell-cell adhesion proteins that are essential for B cell survival and interaction with CD4 T cells. Together, our data reveal temporal features and mechanisms by which IL-10 critically supports humoral immunity during blood-stage Plasmodium infection, information that may be useful for developing new strategies designed to lessen the burden of malaria.
Data availability
All relevant data are within the manuscript and its Supporting Information files and the sequencing data are available in the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE154910.
Files
journal.ppat.1009288.pdf
Files
(9.4 MB)
| Name | Size | Download all |
|---|---|---|
|
Article md5:2de8e4c58a877e0f592e27bbd5341918 |
3.9 MB | Preview Download |
|
Figures md5:23867171184d82df509842aa307b7deb |
5.5 MB | Preview Download |
Additional details
Identifiers
- DOI
- 10.1371/journal.ppat.1009288
- Other
- oai:uchicago.tind.io:5985
Funding
- National Institute of Allergy and Infectious Diseases
- R01AI125446
- National Institute of Allergy and Infectious Diseases
- R01AI127481
- National Institute of Allergy and Infectious Diseases
- T32AI007485
- National Institute of Allergy and Infectious Diseases
- T32AI007511
- National Institute of Allergy and Infectious Diseases
- P01AI097092
- National Institute of Allergy and Infectious Diseases
- HHSN272201400005C
- National Heart, Lung, and Blood Institute
- T32HL007605
- National Science Foundation
- DBI 1559927
- National Center for Research Resources
- S10OD016199
- Australian Research Council
- CE140100011
- National Health and Medical Research Council
- 1113293
- National Health and Medical Research Council
- 1154457
- National Health and Medical Research Council
- 1139486
- National Center for Research Resources
- S10RR025439
- National Cancer Institute
- P30CA086862
- National Center for Research Resources
- S10OD016199