Cytokine-skewed Tfh cells: functional consequences for B cell help.

CD4+ follicular helper T (Tfh) cells play a vital role in providing help for B cells undergoing selection and differentiation into activated antibody-secreting cells in mammalian germinal centers (GCs). Increasing evidence suggests that Tfh cells are a heterogeneous population that generates cytokine-skewed immune responses - a reflection of the microenvironment during differentiation. This has important ramifications for Tfh-mediated B cell help. Because Tfh subsets can have opposing effects on GC B cell responses, we discuss current findings regarding the differentiation and functions of cytokine-skewed Tfh cells in modulating GC B cell differentiation. Antibodies are important weapons against infectious diseases but can also be pathogenic mediators in some autoimmune conditions. Since cytokine-skewed Tfh cells can influence the magnitude and quality of the humoral response, we address the roles of cytokine-skewed Tfh cells in disease.

Mouse Models for Unravelling Immunology of Blood Stage Malaria.

Malaria comprises a spectrum of disease syndromes and the immune system is a major participant in malarial disease. This is particularly true in relation to the immune responses elicited against blood stages of Plasmodium-parasites that are responsible for the pathogenesis of infection. Mouse models of malaria are commonly used to dissect the immune mechanisms underlying disease. While no single mouse model of Plasmodium infection completely recapitulates all the features of malaria in humans, collectively the existing models are invaluable for defining the events that lead to the immunopathogenesis of malaria. Here we review the different mouse models of Plasmodium infection that are available, and highlight some of the main contributions these models have made with regards to identifying immune mechanisms of parasite control and the immunopathogenesis of malaria.

The Systemic and Cellular Metabolic Phenotype of Infection and Immune Response to Listeria monocytogenes.

It is widely accepted that infection and immune response incur significant metabolic demands, yet the respective demands of specific immune responses to live pathogens have not been well delineated. It is also established that upon activation, metabolic pathways undergo shifts at the cellular level. However, most studies exploring these issues at the systemic or cellular level have utilized pathogen associated molecular patterns (PAMPs) that model sepsis, or model antigens at isolated time points. Thus, the dynamics of pathogenesis and immune response to a live infection remain largely undocumented. To better quantitate the metabolic demands induced by infection, we utilized a live pathogenic infection model. Mice infected with Listeria monocytogenes were monitored longitudinally over the course of infection through clearance. We measured systemic metabolic phenotype, bacterial load, innate and adaptive immune responses, and cellular metabolic pathways. To further delineate the role of adaptive immunity in the metabolic phenotype, we utilized two doses of bacteria, one that induced both sickness behavior and protective (T cell mediated) immunity, and the other protective immunity alone. We determined that the greatest impact to systemic metabolism occurred during the early immune response, which coincided with the greatest shift in innate cellular metabolism. In contrast, during the time of maximal T cell expansion, systemic metabolism returned to resting state. Taken together, our findings demonstrate that the timing of maximal metabolic demand overlaps with the innate immune response and that when the adaptive response is maximal, the host has returned to relative metabolic homeostasis.

Development of endocytosis, degradative activity, and antigen processing capacity during GM-CSF driven differentiation of murine bone marrow.

Dendritic cells (DC) are sentinels of the immune system, alerting and enlisting T cells to clear pathogenic threats. As such, numerous studies have demonstrated their effective uptake and proteolytic activities coupled with antigen processing and presentation functions. Yet, less is known about how these cellular mechanisms change and develop as myeloid cells progress from progenitor cells to more differentiated cell types such as DC. Thus, our study comparatively examined these functions at different stages of myeloid cell development driven by the GM-CSF. To measure these activities at different stages of development, GM-CSF driven bone marrow cells were sorted based on expression of Ly6C, CD115, and CD11c. This strategy enables isolation of cells representing five distinct myeloid cell types: Common Myeloid Progenitor (CMP), Granulocyte/Macrophage Progenitor (GMP), monocytes, monocyte-derived Macrophage/monocyte-derived Dendritic cell Precursors (moMac/moDP), and monocyte-derived DC (moDC). We observed significant differences in the uptake capacity, proteolysis, and antigen processing and presentation functions between these myeloid cell populations. CMP showed minimal uptake capacity with no detectable antigen processing and presenting function. The GMP population showed higher uptake capacity, modest proteolytic activity, and little T cell stimulatory function. In the monocyte population, the uptake capacity reached its peak, yet this cell type had minimal antigen processing and presentation function. Finally, moMac/moDP and moDC had a modestly decreased uptake capacity, high degradative capacity and strong antigen processing and presentation functions. These insights into when antigen processing and presentation function develop in myeloid cells during GM-CSF driven differentiation are crucial to the development of vaccines, allowing targeting of the most qualified cells as an ideal vaccine vehicles.