HLA class II (DR0401) molecules induce Foxp3+ regulatory T cell suppression of B cells in Plasmodium yoelii strain 17XNL malaria.

Abstract

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(+) Foxp3(+) T cells (Tregs) that suppressed B cells to secrete antibodies through cell-cell interactions. Treg depletion allowed the DR0401.EA(0) mice to elicit specific antibodies and self-cure the infection. Our results demonstrated a differential role of MHC (HLA) class II molecules in supporting antibody responses to Py17XNL malaria and revealed a new mechanism by which malaria parasites stimulate B cell-suppressogenic Tregs that prevent clearance of infection.

• Authors: Wathsala Wijayalath, Rebecca Danner, Yuliya Kleschenko, Sai Majji, Eileen Franke Villasante, Thomas L Richie, Teodor-Doru Brumeanu, Chella S David, Sofia Casares
• Journal: Infection and immunity (Infect Immun) Vol. 82 Issue 1 Pg. 286-97 (Jan 2014) ISSN: 1098-5522 [Electronic] United States
• PMID: 24166949 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Forkhead Transcription Factors
• Foxp3 protein, mouse
• HLA-DQ Antigens
• HLA-DQ6 antigen
• HLA-DQ8 antigen
• HLA-DR Antigens
• HLA-DR3 Antigen
• HLA-DR4 Antigen

Topics

• Analysis of Variance
• Animals
• B-Lymphocytes (immunology)
• Forkhead Transcription Factors (metabolism)
• HLA-DQ Antigens (immunology)
• HLA-DR Antigens (immunology)
• HLA-DR3 Antigen (immunology)
• HLA-DR4 Antigen (immunology)
• Immunity, Cellular (immunology)
• Immunization
• Malaria (immunology)
• Mice
• Mice, Transgenic
• Plasmodium yoelii (immunology)
• T-Lymphocytes, Regulatory (cytology, immunology)