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

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.

Expression of HLA class II molecules in humanized NOD.Rag1KO.IL2RgcKO mice is critical for development and function of human T and B cells.

BACKGROUND: Humanized mice able to reconstitute a surrogate human immune system (HIS) can be used for studies on human immunology and may provide a predictive preclinical model for human vaccines prior to clinical trials. However, current humanized mouse models show sub-optimal human T cell reconstitution and limited ability to support immunoglobulin class switching by human B cells. This limitation has been attributed to the lack of expression of Human Leukocyte Antigens (HLA) molecules in mouse lymphoid organs. Recently, humanized mice expressing HLA class I molecules have been generated but showed little improvement in human T cell reconstitution and function of T and B cells. METHODS: We have generated NOD.Rag1KO.IL2RγcKO mice expressing HLA class II (HLA-DR4) molecules under the I-E(d) promoter that were infused as adults with HLA-DR-matched human hematopoietic stem cells (HSC). Littermates lacking expression of HLA-DR4 molecules were used as control. RESULTS: HSC-infused HLA-DR4.NOD.Rag1KO.IL-2RγcKO mice developed a very high reconstitution rate (>90%) with long-lived and functional human T and B cells. Unlike previous humanized mouse models reported in the literature and our control mice, the HLA-DR4 expressing mice reconstituted serum levels (natural antibodies) of human IgM, IgG (all four subclasses), IgA, and IgE comparable to humans, and elicited high titers of specific human IgG antibodies upon tetanus toxoid vaccination. CONCLUSIONS: Our study demonstrates the critical role of HLA class II molecules for development of functional human T cells able to support immunoglobulin class switching and efficiently respond to vaccination.

The RTS,S malaria vaccine.

RTS,S is the most advanced candidate vaccine against human malaria. During its remarkable journey from conception and design in the early 1980s to the multicenter Phase 3 trial currently underway across sub-Saharan Africa, RTS,S has overcome tremendous challenges and disproved established vaccine paradigms. In the last several years, Phase 2 studies conducted in infants and children in endemic areas have established the efficacy of RTS,S for reducing morbidity due to clinical malaria. If the results are realized in the Phase 3 trial, the chances for licensure in the near future appear high. Such progress is all the more remarkable given our lack of clear understanding regarding how the vaccine activates the human immune system, the immune correlates of protection or the mechanism whereby a vaccine targeting sporozoites and liver stage parasites can reduce the clinical disease associated with parasitemia. These unanswered questions pose important challenges to be addressed in the quest to understand the protection afforded by RTS,S and to build a more efficacious second generation vaccine against malaria. This review will focus on current knowledge about the protective efficacy of RTS,S and what we have learned regarding its impact on the human immune system.

Immunokinetics of autoreactive CD4 T cells in blood: a reporter for the "hit-and-run" autoimmune attack on pancreas and diabetes progression.

Little is known about the fate of autoreactive CD4 T cells in blood. Using a mouse model for spontaneous autoimmune diabetes we demonstrated that the status of the autoimmune process in pancreas could be pictured through the frequency and phenotype of autoreactive CD4 T cells in the blood. Early during the prediabetic stage, the frequency of these cells in blood decreased as a consequence of their recruitment in the pancreas. This was followed by an imbalance between CD4(+)CD25(+) and CD4(+)CD69(+) T cells in the pancreas that was mirrored in the phenotype of autoreactive T cells in the blood. Waves of activated CD4(+)CD69(+) T cells in blood preceded the disease onset suggesting that the autoimmune attack on pancreas is a discontinuous "hit-and-run" rather than a continuous process. Tracking autoreactive CD4 T cells in blood may help in identifying prediabetic humans and monitoring the disease progression during therapeutic interventions.

Down-regulation of diabetogenic CD4+ T cells by a soluble dimeric peptide-MHC class II chimera.

Type 1 diabetes is an organ-specific autoimmune disease that is mediated by autoreactive T cells. We show here that administration of a soluble dimeric peptide-major histocompatibility complex (pMHC) class II chimera (DEF) to prediabetic double-transgenic mice prevents the onset of disease or, in animals that are already diabetic, restores normoglycemia. The antidiabetogenic effects of DEF rely on the induction of anergy in splenic autoreactive CD4+ T cells via alteration of early T cell receptor signaling and stimulation of interleukin 10-secreting T regulatory type 1 cells in the pancreas. Soluble dimeric pMHC class II may be useful in the development of immunospecific therapies for type 1 diabetes.