After pulmonary virus infection, virus-binding B cells ectopically accumulate in the lung. However, their contribution to protective immunity against reinfecting viruses remains unknown. Here, we show the phenotypes and protective functions of virus-binding memory B cells that persist in the lung following pulmonary infection with influenza virus. A fraction of virus-binding B-cell population in the lung expressed surface markers for splenic mature memory B cells (CD73, CD80, and CD273) along with CD69 and CXCR3 that are up-regulated on lung effector/memory T cells. The lung B-cell population with memory phenotype persisted for more than 5 mo after infection, and on reinfection promptly differentiated into plasma cells that produced virus-neutralizing antibodies locally. This production of local IgG and IgA neutralizing antibody was correlated with reduced virus spread in adapted hosts. Our data demonstrates that infected lungs harbor a memory B-cell subset with distinctive phenotype and ability to provide protection against pulmonary virus reinfection.

Experimental murine infection with the parasites that cause human visceral leishmaniasis (VL) results in the establishment of infection in the liver, spleen, and bone marrow. In most strains of mice, parasites are eventually cleared from the liver, and hepatic resistance to infection results from a coordinated host response involving a broad range of effector and regulatory pathways targeted within defined tissue structures called granulomas. In contrast, parasites persist in the spleen and bone marrow by mechanisms that are less well understood. Parasite persistence is accompanied by the failure of granuloma formation and by a variety of pathologic changes, including splenomegaly, disruption of lymphoid tissue microarchitecture, and enhanced hematopoietic activity. Here, we review the salient features of these distinct tissue responses and highlight the varied roles that cytokines of the tumor necrosis factor family play in immunity to this infection. In addition, we also discuss recent studies aimed at understanding how splenomegaly affects the survival and function of memory cells specific for heterologous antigens, an issue of considerable importance for our understanding of the disease-associated increase in secondary infections characteristic of human VL.

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Streptococcal toxic shock syndrome (STSS) is a severe invasive infection characterized by the sudden onset of shock and multiorgan failure; it has a high mortality rate. Although a number of studies have attempted to determine the crucial factors behind the onset of STSS, the responsible genes in group A Streptococcus have not been clarified. We previously reported that mutations of csrS/csrR genes, a two-component negative regulator system for multiple virulence genes of Streptococcus pyogenes, are found among the isolates from STSS patients. In the present study, mutations of another negative regulator, rgg, were also found in clinical isolates of STSS patients. The rgg mutants from STSS clinical isolates enhanced lethality and impaired various organs in the mouse models, similar to the csrS mutants, and precluded their being killed by human neutrophils, mainly due to an overproduction of SLO. When we assessed the mutation frequency of csrS, csrR, and rgg genes among S. pyogenes isolates from STSS (164 isolates) and non-invasive infections (59 isolates), 57.3% of the STSS isolates had mutations of one or more genes among three genes, while isolates from patients with non-invasive disease had significantly fewer mutations in these genes (1.7%). The results of the present study suggest that mutations in the negative regulators csrS/csrR and rgg of S. pyogenes are crucial factors in the pathogenesis of STSS, as they lead to the overproduction of multiple virulence factors.

CD11c(hi) dendritic cells (DC) play an essential role during the initiation of cell-mediated immunity. Recently, CD11c(lo)CD45RB(hi) DC with regulatory properties have been described. However, the origins of regulatory DC are poorly understood. Here, we show that spleen-derived stromal cells promote selective development of CD11c(lo)CD45RB(+) IL-10-producing regulatory DC from lineage-negative c-kit(+) progenitor cells. These DC have the capacity to suppress T cell responses and induce IL-10-producing regulatory T cells in vitro and to induce antigen-specific tolerance in vivo. Furthermore, stromal cells from mice infected with Leishmania donovani more effectively supported differentiation of these highly potent regulatory DC. The ability of tissue stromal cells to direct the development of DC with a regulatory phenotype thus provides a new mechanism for local immune regulation.

Interaction between dendritic cells (DCs) and T cells is essential for the generation of cell-mediated immunity. Here we show that DCs from mice with chronic Leishmania donovani infection fail to migrate from the marginal zone to the periarteriolar region of the spleen. Stromal cells were fewer, which was associated with loss of CCL21 and CCL19 expression. The residual stromal cells and endothelium produced sufficient CCL21 to direct the migration of DCs transferred from naïve mice. However, DCs from infected mice had impaired migration both in naïve recipients and in vitro, in response to CCL21 and CCL19. Defective localization was attributable to tumor necrosis factor-alpha-dependent, interleukin 10-mediated inhibition of CCR7 expression. Effective immunotherapy was achieved with CCR7-expressing DCs, without the need to identify protective Leishmania antigens. Thus defective DC migration plays a major role in the pathogenesis of this disease and the immunosuppression is mediated, at least in part, through the spatial segregation of DCs and T cells.

The development of secondary lymphoid organs is a highly regulated process, mediated by tumor necrosis factor (TNF) family cytokines. In contrast, the mechanisms controlling changes in lymphoid architecture that occur during infectious disease are poorly understood. Here we demonstrate that during infection with Leishmania donovani, the marginal zone of mice undergoes extensive remodeling, similar in extent to developmental abnormalities in mice lacking some TNF family cytokines. This process is selective, comprising a dramatic and rapid loss of marginal zone macrophages (MZMs). As a functional consequence, lymphocyte traffic into the white pulp is impaired during chronic leishmaniasis. Significantly, MZMs were preserved in L. donovani-infected B6.TNF-alpha(-/-) mice or mice that received anti-TNF-alpha antibodies, whereas studies in CD8(+) T-cell-deficient mice and in mice lacking functional CD95L, excluded a direct role for either cytotoxic T lymphocyte activity or CD95-mediated apoptosis in this process. Loss of MZMs was independent of parasite burden, yet could be partially prevented by chemotherapy, which in turn reduced endogenous TNF-alpha levels. This is the first report of an infectious agent causing selective and long-lasting changes to the marginal zone via TNF-alpha-mediated mechanisms, and illustrates that those cytokines involved in establishing lymphoid architecture during development, may also play a role in infection-induced lymphoid tissue remodeling.

The major predisposing factor for melioidosis is diabetes mellitus, but no immunological mechanisms have been investigated to explain this. In this study, polymorphonuclear neutrophil (PMN) responses to Burkholderia pseudomallei, the causative agent of melioidosis, in healthy and diabetic Thai subjects were determined by flow cytometry. The results showed that B. pseudomallei displayed reduced uptake by PMNs compared to Salmonella enterica serovar Typhimurium and Escherichia coli. Additionally, intracellular survival of B. pseudomallei was detected throughout a 24-h period, indicating the intrinsic resistance of B. pseudomallei to killing by PMNs. Moreover, PMNs from diabetic subjects displayed impaired phagocytosis of B. pseudomallei, reduced migration in response to interleukin-8, and an inability to delay apoptosis. These data show that B. pseudomallei is intrinsically resistant to phagocytosis and killing by PMNs. These observations, together with the impaired migration and apoptosis in diabetes mellitus, may explain host susceptibility in melioidosis.