Phillip Scott

Leishmaniasis: complexity at the host–pathogen interface

Leishmania is a genus of protozoan parasites that are transmitted by the bite of phlebotomine sandflies and give rise to a range of diseases (collectively known as leishmaniases) that affect over 150 million people worldwide. Cellular immune mechanisms have a major role in the control of infections with all Leishmania spp. However, as discussed in this Review, recent evidence suggests that each host–pathogen combination evokes different solutions to the problems of parasite establishment, survival and persistence. Understanding the extent of this diversity will be increasingly important in ensuring the development of broadly applicable vaccines, drugs and immunotherapeutic interventions.

Role of Cytokines and CD4+ T‐Cell Subsets in the Regulation of Parasite Immunity and Disease

CD4+ T cells have been separated into two subsets, designated TH1 and TH2, based upon the repertoire of lymphokines that they produce following stimulation. We have analyzed the role of these T-cell subsets in two chronic parasitic infections, leishmaniasis and schistosomiasis. In both diseases, we found a strong association with TH1 stimulation and protection, and TH2 stimulation and immunopathology. In addition, certain parasite antigens appeared to be strongly linked with either TH1 or TH2 cell development. This led to the establishment of protective T-cell lines and clones in a L. major model, from which we identified a new candidate antigen for vaccination against Leishmania parasites. Moreover, we show that protection against L. major infection can be significantly augmented by coadministration of IFN-gamma with antigen, a lymphokine known to inhibit TH2 cell proliferation. In S. mansoni-infected mice, animals with a patent infection exhibit an overwhelming TH2 response, while animals protectively immunized with irradiated cercariae preferentially produce IFN-gamma, a lymphokine associated with TH1 cell stimulation. In addition, we show that ablation of schistosome-induced eosinophilia by in vivo anti-IL-5 monoclonal treatment fails to reduce the protection induced by irradiated cercariae. Similarly, anti-IL-5 treatment resulted in egg-induced granulomas nearly devoid of eosinophils, but only caused a marginal reduction in granuloma size. These results demonstrate that an understanding of the factors controlling TH1 and TH2 development will significantly facilitate the identification and development of vaccines for parasitic infections.

The role of T-cell subsets and cytokines in the regulation of infection

The study of immunity to infectious agents has proved valuable for analysing the role of T-cell subsets. This was true when Zinkernagel and Doherty demonstrated MHC restriction using viral and bacterial systems, and was re-emphasized at a recent meeting, where data were presented on the role of T cells and cytokines in viral, bacterial, protozoan and helminth infections. This report summarizes some of the highlights.

Central memory T cells mediate long-term immunity to Leishmania major in the absence of persistent parasites

Infection with Leishmania major induces a protective immune response and long-term resistance to reinfection, which is thought to depend upon persistent parasites. Here we demonstrate that although effector CD4+ T cells are lost in the absence of parasites, central memory CD4+ T cells are maintained. Upon secondary infection, these central memory T cells become tissue-homing effector T cells and mediate protection. Thus, immunity to L. major is mediated by at least two distinct populations of CD4+ T cells: short-lived pathogen-dependent effector cells and long-lived pathogen-independent central memory cells. These data suggest that central memory T cells should be the targets for nonlive vaccines against infectious diseases requiring cell-mediated immunity.

Role of Cytokines in the Differentiation of CD4+ T-Cell Subsets in vivo

The realization during the past few years that CD4+ T cells (TH cells) can be subdivided into distinct subsets on the basis of both function and cytokine expression (Mosmann & Coffman 1987, 1989) has helped clarify a number of outstanding questions in immunology. One such question, for example, is whether B-ceil help and delayed-type hypersensitivity (DTH) are mediated by the same type of T cell. Not surprisingly, this revised view of TH cells has raised a new series of questions aboul T cell-mediated regulatory and effector functions. Among the most interesting, and perhaps complex, of the questions are: From what precursors do THI and TH2 cells arise? and: What factors regulate this differentiation process?

Helper T-cell subsets in mouse leishmaniasis: induction, expansion and effector function

It has been a surprise to find that the two distinct subsets of mouse CD4+ T cells identified from clones cultured in vitro also occur during Leishmania infection. The spectrum of disease encountered during these infections ranges from successful resolution to fatal dissemination and in mice these outcomes are accompanied by expansion of TH1 or TH2 CD4+ cells, respectively. This review focuses on the mechanisms that cause such disparate responses to the parasite.

TRAF6 Is a Critical Factor for Dendritic Cell Maturation and Development

IL-1 receptor (IL-1R)/Toll-like receptor (TLR) family and TNF receptor (TNFR) superfamily members are critical for regulating multiple aspects of dendritic cell (DC) biology. Several signaling pathways associated with each family utilize the adapter molecule, TRAF6, but its role in DCs is unclear. By examining TRAF6-deficient mice and bone marrow (BM) chimeras reconstituted with TRAF6-deficient fetal liver cells, we show that proper DC maturation requires TRAF6. In response to either microbial components or CD40L, TRAF6-deficient DCs fail to upregulate surface expression of MHCII and B7.2, or produce inflammatory cytokines. Moreover, LPS-treated TRAF6-deficient DCs do not exhibit an enhanced capacity to stimulate naive T cells. Interestingly, a major population of splenic DCs, the CD4(+)CD8alpha(-) subset, is nearly absent in both TRAF6-deficient mice and BM chimeras. Together these results indicate that TRAF6 regulates the critical processes required for maturation, activation, and development of DCs, the primary cellular bridge between innate and adaptive immunity.

The role of interleukin 12 in the immune response, disease and therapy

The heterodimeric cytokine interleukin 12 (IL-12) stimulates cytotoxicity and cytokine production by T cells and natural killer (NK) cells, and initiates development of CD4+ T helper 1 (Th1) cells. A recent meeting defined how IL-12 contributes to immune responses in disease, as well as how IL-12 can be used to circumvent disease.

The IL-27 Receptor (WSX-1) Is an Inhibitor of Innate and Adaptive Elements of Type 2 Immunity

Although previous studies have investigated the role of IL-27/WSX-1 interactions in the regulation of Th1 responses, little is known about their role in regulating Th2-type responses. Studies presented in this work identify a direct role for IL-27/WSX-1 interactions in the negative regulation of type 2 responses independent of effects on type 1 cytokines. WSX-1−/− mice infected with the gastrointestinal helminth Trichuris muris displayed accelerated expulsion of parasites and the development of exaggerated goblet cell hyperplasia and mastocytosis in the gut due to increased production of Th2 cytokines. Enhanced mast cell activity in the absence of WSX-1 was consistent with the ability of wild-type mast cells to express this receptor. In addition, IL-27 directly suppressed CD4+ T cell proliferation and Th2 cytokine production. Together, these studies identify a novel role for IL-27/WSX-1 in limiting innate and adaptive components of type 2 immunity at mucosal sites.

The role of natural killer cells in host—parasite interactions

Natural killer cells contribute to resistance to infectious organisms, and may also influence the nature of the adaptive immune response associated with infection. During the past year, their role in these events has been more clearly defined. In addition, the results of several recent studies that have begun to define the mechanisms by which natural killer cells recognize their targets will be important in further elucidating their role in infectious disease.