TY - JOUR
T1 - CD28 deficiency leads to accumulation of germinal-center independent IgM+ experienced B cells and to production of protective IgM during experimental malaria
AU - da Silva, Henrique Borges
AU - de Salles, Érika Machado
AU - Lima-Mauro, Eliana Faquim
AU - Sardinha, Luiz Roberto
AU - Álvarez, José Maria
AU - Lima, Maria Regina D.Império
N1 - Funding Information:
Funding:ThisworkwassupportedbySãoPaulo ResearchFoundation(FAPESP,Brazil)grants, 2010/51150-4,2013/07140-2and2015/20432-8 (MRDIL),andNationalCouncilforScientificand TechnologicalDevelopment(CNPq,Brazil)grants, 303676/2014-0and448765/2014-4(MRDIL).
Funding Information:
This work was supported by São Paulo Research Foundation (FAPESP, Brazil) grants, 2010/51150-4, 2013/07140-2 and 2015/20432-8 (MRDIL), and National Council for Scientific and Technological Development (CNPq, Brazil) grants, 303676/2014-0 and 448765/2014-4 (MRDIL). HBdS received a PhD fellowship from FAPESP (2009/08559-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2018 Borges da Silva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2018/8
Y1 - 2018/8
N2 - Protective immunity to blood-stage malaria is attributed to Plasmodium-specific IgG and effector-memory T helper 1 (Th1) cells. However, mice lacking the costimulatory receptor CD28 (CD28KO) maintain chronic parasitemia at low levels and do not succumb to infection, suggesting that other immune responses contribute to parasite control. We report here that CD28KO mice develop long-lasting non-sterile immunity and survive lethal parasite challenge. This protection correlated with a progressive increase of anti-parasite IgM serum levels during chronic infection. Serum IgM from chronically infected CD28KO mice recognize erythrocytes infected with mature parasites, and effectively control Plasmodium infection by promoting parasite lysis and uptake. These antibodies also recognize autoantigens and antigens from other pathogens. Chronically infected CD28KO mice have high numbers of IgM+ plasmocytes and experienced B cells, exhibiting a germinal-center independent Fas+GL7-CD38+CD73- phenotype. These cells are also present in chronically infected C57BL/6 mice although in lower numbers. Finally, IgM+ experienced B cells from cured C57BL/6 and CD28KO mice proliferate and produce anti-parasite IgM in response to infected erythrocytes. This study demonstrates that CD28 deficiency results in the generation of germinal-center independent IgM+ experienced B cells and the production of protective IgM during experimental malaria, providing evidence for an additional mechanism by which the immune system controls Plasmodium infection.
AB - Protective immunity to blood-stage malaria is attributed to Plasmodium-specific IgG and effector-memory T helper 1 (Th1) cells. However, mice lacking the costimulatory receptor CD28 (CD28KO) maintain chronic parasitemia at low levels and do not succumb to infection, suggesting that other immune responses contribute to parasite control. We report here that CD28KO mice develop long-lasting non-sterile immunity and survive lethal parasite challenge. This protection correlated with a progressive increase of anti-parasite IgM serum levels during chronic infection. Serum IgM from chronically infected CD28KO mice recognize erythrocytes infected with mature parasites, and effectively control Plasmodium infection by promoting parasite lysis and uptake. These antibodies also recognize autoantigens and antigens from other pathogens. Chronically infected CD28KO mice have high numbers of IgM+ plasmocytes and experienced B cells, exhibiting a germinal-center independent Fas+GL7-CD38+CD73- phenotype. These cells are also present in chronically infected C57BL/6 mice although in lower numbers. Finally, IgM+ experienced B cells from cured C57BL/6 and CD28KO mice proliferate and produce anti-parasite IgM in response to infected erythrocytes. This study demonstrates that CD28 deficiency results in the generation of germinal-center independent IgM+ experienced B cells and the production of protective IgM during experimental malaria, providing evidence for an additional mechanism by which the immune system controls Plasmodium infection.
UR - http://www.scopus.com/inward/record.url?scp=85052649016&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052649016&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0202522
DO - 10.1371/journal.pone.0202522
M3 - Article
C2 - 30148845
AN - SCOPUS:85052649016
VL - 13
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 8
M1 - e0202522
ER -