HLA Class II (DR0401) Molecules Induce Foxp3⁺Regulatory T Cell Suppression of B Cells in Plasmodium yoelii Strain 17XNL Malaria

Abstract

c Unlike human malaria parasites that induce persistent infection, some rodent malaria parasites, like Plasmodium yoelii strain 17XNL (Py17XNL), induce a transient (self-curing) malaria infection. Cooperation between CD4 T cells and B cells to produce antibodies is thought to be critical for clearance of Py17XNL parasites from the blood, with major histocompatibility complex (MHC) class II molecules being required for activation of CD4 T cells. In order to better understand the correspondence between murine malaria models and human malaria, and in particular the role of MHC (HLA) class II molecules, we studied the ability of humanized mice expressing human HLA class II molecules to clear Py17XNL infection. We showed that humanized mice expressing HLA-DR4 (DR0401) molecules and lacking mouse MHC class II molecules (EA 0 ) have impaired production of specific antibodies to Py17XNL and cannot cure the infection. In contrast, mice expressing HLA-DR4 (DR0402), HLA-DQ6 (DQ0601), HLA-DQ8 (DQ0302), or HLA-DR3 (DR0301) molecules in an EA 0 background were able to elicit specific antibodies and self-cure the infection. In a series of experiments, we determined that the inability of humanized DR0401.EA 0 mice to elicit specific antibodies was due to expansion and activation of regulatory CD4 ؉

Nonobese Diabetic (NOD) Mice Lack a Protective B-Cell Response against the “Nonlethal”Plasmodium yoelii17XNL Malaria Protozoan

“…Expression of HLA-DRB1 ∗ 04  alleles has been linked in particular to severe malaria in Gabon and Northern Ghana [3, 4], while the HLA-DRB1 ∗ 1302, HLA-DRB1 ∗ 0101, and HLA-DQB1 ∗ 0501  suballeles have been associated with resistance to severe malaria in The Gambia, Western Kenya, Gabon, and Vietnam [5–8]. In agreement with human studies, we found that, indeed, humanized HLA-DR4 (DRB1 ∗ 0401) mouse lacking murine MHC class II molecules (EA 0 ) have impaired production of protective antibodies to nonlethal P. yoelii 17XNL strain of malaria, and they succumbed shortly after infection [9]. …”

“…Live sporozoites were obtained from the salivary glands of P. yoelii -infected Anopheles stephensi mosquitoes as we previously described [9]. NOD mice and C57BL/6 mice were challenged retroorbitally with 100 P. yoelii 17XNL live sporozoites per mouse.…”

“…Mice show parasitemia shortly upon sporozoites challenge; they gradually develop high titers of antibodies to infected red blood cells (iRBCs) and, as a consequence, they are able to self -cure the blood stage infection within 4 to 7 weeks, depending on the sporozoites load and genetic background [9]. In contrast, the NOD mice were unable to mount an antibody response to iRBCs, and they all succumbed shortly after infection.…”

Preserved Dendritic Cell HLA-DR Expression and Reduced Regulatory T Cell Activation in Asymptomatic Plasmodium falciparum and P. vivax Infection

“…Continued Treg cell expansion negatively impacts immune control of the infection (42), with Treg cell activation resulting in increased suppression of T cell responses (43). In humanized mice expressing HLA-DR0401, Treg cell activation has been associated with suppression of protective anti-parasitic antibody responses (44) and failure to control parasite growth.…”

Myeloperoxidase Attenuates Pathogen Clearance during Plasmodium yoelii Nonlethal Infection

“…The control of the symptomatic blood-stage infection by the host requires the innate and the adaptive immune systems (1, 2). Using mouse models, it was shown that macrophages (3), CD4 ϩ T cells (4-6), and B cells (7,8) are essential for effective parasite clearance. However, an effective immune activation and regulation is necessary for rapid parasite control and for the prevention of host pathology (5, 9).…”