γδ T cells constitute the third arm of a tripartite adaptive immune system in jawed vertebrates, besides αβ T cells and B cells. Like the other two lymphocyte-types, they express diverse antigen receptors, capable of specific ligand recognition. Functionally, γδ T cells represent a system of differentiated subsets, sometimes engaged in cross-regulation, which ultimately determines their effect on other components of the immune system, including B cells and antibodies. γδ T cells are capable of providing help to B cells in antibody production. More recently it became clear that γδ T cells influence B cell differentiation during the peripheral stages of B cell development, control levels of circulating immunoglobulin (all subclasses), and affect production of autoantibodies. Because of this relationship between γδ T cells and B cells, the extensive variation of γδ T cells among human individuals might be expected to modulate their humoral responsiveness.

Autoinflammatory disease and hyperinflammatory syndromes represent a growing number of diseases associated with inappropriately controlled inflammation in multiple organs. Systemic inflammation commonly results from dysregulated activation of innate immune cells, and therapeutic targeting of the IL-1β pathway has been used to ameliorate some of these diseases. Some hyperinflammatory syndromes, however, such as hemophagocytic lymphohistiocytosis and the newly classified proteasome disability syndromes, are refractory to such treatments, suggesting that other factors or environmental stressors may be contributing. In comparing two cytokine reporter mouse strains, we identify IFN-γ as a mediator of systemic autoinflammatory disease. Chronically elevated levels of IFN-γ resulted in progressive multiorgan inflammation and two copies of the mutant allele resulted in increased mortality accompanied by myeloproliferative disease. Disease was alleviated by genetic deletion of T-bet. These studies raise the possibility that therapeutics targeting the IFN-γ pathway might be effective in hyperinflammatory conditions refractory to IL-1β-targeted therapies.

Natural killer (NK) and NK T cells are tissue lymphocytes that secrete cytokines rapidly upon stimulation. Here, we show that these cells maintain distinct patterns of constitutive cytokine mRNAs. Unlike conventional T cells, NK T cells activate interleukin (IL)-4 and interferon (IFN)-gamma transcription during thymic development and populate the periphery with both cytokine loci previously modified by histone acetylation. Similarly, NK cells transcribe and modify the IFN-gamma gene, but not IL-4, during developmental maturation in the bone marrow. Lineage-specific patterns of cytokine transcripts predate infection and suggest evolutionary selection for invariant but distinct types of effector responses among the earliest responding lymphocytes.

Hepatitis B virus (HBV) is a major human pathogen that causes immune-mediated hepatitis. Successful immunity to HBV is age dependent: viral clearance occurs in most adults, whereas neonates and young children usually develop chronic infection. Using a mouse model of HBV infection, we sought mechanisms underpinning the age-dependent outcome of HBV and demonstrated that hepatic macrophages facilitate lymphoid organization and immune priming within the adult liver and promote successful immunity. In contrast, lymphoid organization and immune priming was greatly diminished in the livers of young mice, and of macrophage-depleted adult mice, leading to abrogated HBV immunity. Furthermore, we found that CXCL13, which is involved in B lymphocyte trafficking and lymphoid architecture and development, is expressed in an age-dependent manner in both adult mouse and human hepatic macrophages and plays an integral role in facilitating an effective immune response against HBV. Taken together, these results identify some of the immunological mechanisms necessary for effective control of HBV.

The four LEP collaborations, ALEPH, DELPHI, L3 and OPAL, have searched for the neutral Higgs bosons which are predicted by the Minimal Supersymmetric standard model (MSSM). The data of the four collaborations are statistically combined and examined for their consistency with the background hypothesis and with a possible Higgs boson signal. The combined LEP data show no significant excess of events which would indicate the production of Higgs bosons. The search results are used to set upper bounds on the cross-sections of various Higgs-like event topologies. The results are interpreted within the MSSM in a number of "benchmark" models, including CP-conserving and CP-violating scenarios. These interpretations lead in all cases to large exclusions in the MSSM parameter space. Absolute limits are set on the parameter tan β and, in some scenarios, on the masses of neutral Higgs bosons.