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  • Review Article
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The immunology of susceptibility and resistance to Leishmania major in mice

Nature Reviews Immunology volume 2, pages 845–858 (2002)Cite this article

Key Points

  • The early production of interleukin-4 (IL-4) by an oligoclonal population of CD4+ T cells that recognize the Leishmania antigen LACK (Leishmania homologue of receptors for activated C kinase) is responsible, at least in part, for T helper 2 (TH2)-cell polarization and susceptibility to L. major infection in BALB/c mice.

  • As an early IL-4 response, including production by LACK-reactive cells, has been a relatively consistent finding in L. major-resistant mouse strains also, the ability to redirect an early TH2 response seems to be the most probable determinant of resistance in the mouse model.

  • On the basis of studies in anti-IL-12 antibody-treated or IL-12-knockout resistant-background mice, and in BALB/c mice treated with IL-12 at the time of challenge, it seems that the onset of IL-12 production by dendritic cells (DCs) is key to the redirection of the T-cell response and the development of acquired resistance.

  • Selective loss of IL-12 signalling owing to downregulated expression of the IL-12 receptor β2-chain has been proposed to explain the inability of BALB/c mice to over-ride the early TH2 response. Alternatively, owing to the rapid dissemination of parasites to the viscera in BALB/c mice, distinct populations of DCs with a preferential capacity to prime TH2 cells in these tissues might be involved in maintaining TH2 responses during infection.

  • Under some circumstances — for example, with particular L. major substrains — IL-4 and/or IL-4-receptor signalling are not required to promote TH2-cell development and susceptibility in BALB/c mice. IL-13, transforming growth factor-β and, in particular, IL-10 have each been shown to inhibit the generation or expression of L. major-specific immunity, and regardless of parasite substrain, ablation of the activity of many type-2 cytokines confers greater resistance than the ablation of just one, including IL-4.

  • More-natural models of L. major infection, involving low-dose inoculation of the skin, have revealed a requirement for CD8+ T cells for primary immunity in resistant mice. The maintenance of immunity in healed mice requires persistent antigen and IL-12 production, which provides a rationale for DNA vaccines or live, attenuated vaccines to confer long-lasting protection.

  • The persistence of L. major after healing in resistant mice was shown to be controlled by IL-10 produced by CD4+CD25+CD45RBlow regulatory T cells, which draws a link with the IL-4- and IL-10-producing CD4+CD45RBlow T-cell subset that was shown to suppress L. major immunity in BALB/c mice. Susceptibility, therefore, might not be due to a TH2 bias per se, but to an imbalance in the number of regulatory T cells that are activated during infection in BALB/c mice.

Abstract

Established models of T-helper-2-cell dominance in BALB/c mice infected with Leishmania major — involving the early production of interleukin-4 by a small subset of Leishmania-specific CD4+ T cells — have been refined by accumulating evidence that this response is not sufficient and, under some circumstances, not required to promote susceptibility. In addition, more recent studies in L. major-resistant mice have revealed complexities in the mechanisms responsible for acquired immunity, which necessitate the redesign of vaccines against Leishmania and other pathogens that require sustained cell-mediated immune responses.

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Figure 1: Life cycle of Leishmania major infection.
Figure 2: The genetics of resistance to Leishmania major.
Figure 3: Model of TH1-/TH2-cell development.
Figure 4: Early events in susceptible and resistant mice.
Figure 5: Late events in susceptible mice.
Figure 6: Late events in resistant mice.

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Acknowledgements

We thank A. Sher and D. Jankovic for critical review of the manuscript.

Author information

Authors and Affiliations

  1. Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    David Sacks

  2. Department of Immunology, George Washington University, 2300 Eye Street, Washington, 20037, DC, USA

    Nancy Noben-Trauth

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  1. David Sacks
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  2. Nancy Noben-Trauth
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Correspondence to David Sacks.

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DATABASES

LocusLink

β2-microglobulin

B7

Bcl-6

CCR2

CD8

CD28

CD40

CD40L

c-MAF

CTLA4

Fas

FasL

FOG1

GATA3

IFN-γ

IFN-γR

IL-4

IL-4Rα

IL-10

IL-10R

IL-12

IL-12 p40

IL-12Rβ1

IL-12Rβ2

IL-13

IL-13Rα2

IL-18

iNOS

MCP1

NFAT-c

OX40

OX40L

ROG

STAT1

STAT4

STAT6

T-bet

TGF-β

TGF-β receptor type II

TNF

TNFR1

TNFR2

WSX1

Swiss-Prot

GFP

FURTHER INFORMATION

Mouse Genome Informatics

Glossary

T HELPER 1/T HELPER 2

(TH1/TH2). A classification of CD4+ T cells on the basis of the patterns of cytokines that they secrete. TH1 cells secrete large amounts of IFN-γ and associated pro-inflammatory cytokines. TH2 cells secrete large amounts of IL-4 and associated cytokines that promote antibody production by B cells. TH1/TH2 cytokines can cross-regulate each other's responses. An imbalance of TH1/TH2 responses is thought to contribute to the pathogenesis of various infections, allergic responses and autoimmune diseases.

IL-4 REPORTER MICE

Genetically engineered knock-in mice in which the gene encoding IL-4 has been replaced by sequences that encode a reporter molecule, such as green fluorescent protein (GFP). When the IL-4 promoter region is activated, GFP is expressed and living cells can be visualized by flow cytometry.

MHC CLASS II TETRAMERS

A method of visualizing antigen-specific CD4+ T cells by flow cytometry. Typically, four MHC class II molecules with their associated peptides are held together by streptavidin, which has four binding sites for biotin, which is attached to the tail of the MHC molecule. These four peptide–MHC complexes (tetramers) can bind peptide-specific T-cell receptors. The streptavidin molecules are often labelled with a fluorochrome so that binding can be assessed by flow cytometry. Similarly, MHC class I tetramers can be engineered to track CD8+ T-cell receptors.

SEVERE COMBINED IMMUNODEFICIENCY

(SCID). Mice of this phenotype lack functional T and B cells owing to a spontaneous mutation in the Prkdc gene (protein kinase, DNA activated, catalytic polypeptide) located on chromosome 16. These mice are often used for the reconstitution of T-cell subsets to study their functions in vivo.

REACTIVE NITROGEN INTERMEDIATES

(RNIs). Primarily nitric oxide, these are generated by nitrogen oxidation of l-arginine, and can have potent activity to destroy intracellular pathogens such as Leishmania.

CD4+CD25+CD45RBLOW REGULATORY T CELLS

A specialized subset of CD4+ T cells that can suppress other T-cell responses. These cells are characterized by expression of the IL-2 receptor β-chain (CD25). In some instances, suppression has been associated with the secretion of IL-10, TGF-β or both.

SAFE-TARGET MODEL

A model to explain the role of cell types such as fibroblasts, which L. major parasites might infect and replicate in without activating immune responses.

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Sacks, D., Noben-Trauth, N. The immunology of susceptibility and resistance to Leishmania major in mice. Nat Rev Immunol 2, 845–858 (2002). https://doi.org/10.1038/nri933

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