Murine cutaneous leishmaniasis : Susceptibility correlates with differential expansion of helper T-cell subsets

Locksley, Richard M.; Heinzel, Frederick P.; Sadick, Michael D.; Holaday, B J; Gardner, Kelly

doi:10.1016/s0769-2625(87)80030-2

Cited by 186 publications

(150 citation statements)

References 16 publications

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“…IL-4 and IL-10 expression have been used as indicators of a Th2-type response implicated in disease exacerbation, while IFN-g and IL-12 are the cytokines associated with the Th1-type response and cure. 3,18,19 We wished to investigate whether differences in the cytokine response to intradermal infection at the base of the tail could be observed in mice congenic for three disease susceptibility loci that we have identified and named lmr1-3. 9,10 Differences in response attributed to the lmr loci could then provide some clues as to the mechanism involved in their effect on the disease outcome.…”

Section: Discussionmentioning

confidence: 99%

Dissociation of disease susceptibility, inflammation and cytokine profile in lmr1/2 congenic mice infected with Leishmania major

et al. 2004

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Severity of disease caused by Leishmania major depends on the genetics of the host. Early induction of T helper cell type 1 (Th1)-type responses in resistant C57BL/6 mice and T helper cell type 2 (Th2) in susceptible BALB/c mice is thought to determine cure or disease respectively. We have mapped three loci that confer susceptibility or resistance upon congenic mice on the C57BL/6 or BALB/c backgrounds. Here we examine the histopathology and production of interleukin 4 (IL-4) and interferon gamma (IFN-g) in the skin and draining lymph nodes in the congenic and parental mice. We show an evolving granuloma with a staged infiltration of inflammatory cells, but no difference between the groups. As an indication of an earlypolarised Th1/Th2 response we measured IFN-g and IL-4 in the lymph nodes and found no difference between any of the mice during the first 48 h. During infection, the level of IL-4 correlated with the lesion size, indicating that IL-4 reflects the disease severity rather than controls it. Considering this effect, B6.C(lmr1,lmr2) mice had similar cytokine levels to the parental C57BL/ 6 mice despite increased susceptibility and C.B6(lmr1,lmr2) were similar to BALB/c despite increased resistance. We conclude that the lmr loci affect disease severity by a mechanism independent of conventional helper T-cell responses. Genes and Immunity (2004) IntroductionThe first demonstration that the balance of T helper cell responses determines the severity of the pathology in an infectious disease model came from studies on murine cutaneous leishmaniasis caused by infection with Leishmania major. A large number of studies have shown that susceptibility to disease in BALB/c mice correlated with the dominance of interleukin 4 (IL-4)-driven T helper cell type 2 (Th2)-type responses, while resistance in C57BL/6 mice correlated with the dominance of interferon gamma (IFN-g)-driven T helper cell type 1 (Th1) responses. 1,2 However, as pointed out by Sacks and Noben-Trauth, 3 the simplicity of this model has begun to be challenged. For example, there are data indicating that IL-4 is not sufficient to mediate progressive disease, 4 nor is it essential for the induction of Th2 responses 5 and ablation of IL-4 or IL-4 signaling in BALB/c mice does not necessarily lead to resistance. 6 Studies are underway in many laboratories to map the genes that determine susceptibility to leishmaniasis in the expectation that they may help identify mechanisms of polarisation of the T helper cell responses. Although linkage to L. major response phenotypes has been mapped to loci on chromosomes 5, 6, 9, 10, 11, 15, 17 and X, 7-11 the relationship between these loci and the control of the polarisation of T cell responses in response to L. major has not been determined.We used a genome-wide scan on two large populations of F2 mice created from a cross between the susceptible BALB/c and the resistant C57BL/6 strains, and showed that susceptibility to disease caused by intradermal infection at the base of the tail with L. major is controlle...

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Section: Discussionmentioning

confidence: 99%

Dissociation of disease susceptibility, inflammation and cytokine profile in lmr1/2 congenic mice infected with Leishmania major

et al. 2004

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“…9 In addition to work carried out on the genetics of host response to L. major, this system has long fascinated immunologists because a marked polarisation in the immune response is observed upon challenge with L. major parasites. BALB/c produces T helper (Th)2-type cytokines, in particular IL-4, which has been shown to be associated with disease progression and susceptibility, 13 whereas recovery from infection in resistant C57BL/6 depends critically upon the induction of a Th1-type response resulting in the activation of macrophages to kill the intracellular organisms. 14,15 This has led to the intensive study of the regulators of the polarised Th1/Th2 helper T-cell responses by immunologists.…”

Section: Introductionmentioning

confidence: 99%

Leishmaniasis host response loci (lmr1–3) modify disease severity through a Th1/Th2-independent pathway

et al. 2003

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“…According to this hypothesis, small numbers of L3T4 + cells would behost protective, whereas excessive numbers of the same cell type would have adetrimental effect. However, there is increasing evidence supporting the alternative possibility that resistance to disease or its abrogation are induced by distinct subsets of L3T4+ cells [8,39,40]. In particular, a recent study by Locksley et al [8] has provided direct evidence for differences in lymphokine production by lymphocytes from healer and those from nonhealer mice infected with L. major.…”

Section: Discussionmentioning

confidence: 99%

“…However, there is increasing evidence supporting the alternative possibility that resistance to disease or its abrogation are induced by distinct subsets of L3T4+ cells [8,39,40]. In particular, a recent study by Locksley et al [8] has provided direct evidence for differences in lymphokine production by lymphocytes from healer and those from nonhealer mice infected with L. major. The findings are consistent with the interpretation that inability to control cutaneous disease is reflected by expansion of type 2 T helper cells (TH2), whereas effective cellular immunity is accompanied by expansion of type 1 T helper cells (THl}.…”

Section: Discussionmentioning

confidence: 99%

“…resistance to L. major infection in nude recipients, whereas T cells from mice chronically infected with L. major generally not only fail to mediate protection, but can totally abrogate the host-protective effect of normal mouse lymphocytes [5]o T cells from uninfected mice with resistance-promoting activity and T cells from chronically infected mice with disease-promoting activity both express the L3T4+Ly-2-phenotypeo Previous studies have indicated functional heterogeneity of L3T4 + cells, showing that antigen-specific and major histocompatibility complex (MHC) class 11-restricted cloned murine T helper (Tb) cells of this phenotype give rise to differential pattems of lymphokine production [6,7)o The L3T4+ T cell clones were classified into two categories {7], designated Tßl, producing interleukin (IL) 2 and interferon-y (IFN-y), and TH2, produclog IL 4and IL 5. The different roles of these T cell types in the pathogenesis of L. major infections was suggested by the recent studies of Locksley et al [8], which showed lymph node cells (LNC) from ·healer mice to be high producers of IFN-y and those from nonhealer mice to release only minimal amounts of the same lymphokineo On the other band, only lymphoid cells from nonhealer mice contained IL 4 mRNAo Patterns of lymphokine production allow the identification of functionally distinct L3T4 + cellso However, it would be particularly useful tobe able to distinguish L3T4+ subsets on the basis of surface antigen expression, since this would allow their separation and functional characterization. Furthermore, it could facilitate the isolation of T cell clones with defined activities.…”

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confidence: 98%

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L3T4 T cells promoting susceptibility to murine cutaneous leishmaniasis express the surface marker Ly‐24 (Pgp‐1)

Moll¹,

Scollay²

1989

Eur J Immunol

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In a murine model of cutaneous leishmaniasis, the importance of T cell‐dependent immunity has been documented by the susceptibility to parasite infection of athymic nude mice of both genetically resistant and genetically susceptible strains. T lymphocytes from uninfected mice have the capacity to promote resistance to Leishmania major infection in nude recipients, whereas T cells from mice chronically infected with L. major not only fail to mediate protection, but totally abrogate the host‐protective effect of normal mouse lymphocytes. Both these effects are mediated by T cells which have the phenotype L3T4Ly‐2‐. To discriminate between the two activities, we have tried to separate the L3T4 population on the basis of additional cell surface markers and we have found that peripheral L3T4 lymphocytes could be subdivided according to their expression of the Ly‐24 (Pgp‐1) surface marker. In adoptive transfer experiments, both the Ly‐24 and the Ly‐24 subset of L3T4 cells from uninfected mice had the capacity to mediate resistance to infection with L. major. However, diseasepromoting activity was only found in the L3T4Ly‐24 and not in the L3T4Ly‐24‐ subset of cells from mice with chronic cutaneous disease. Moreover, Ly‐24 expression was strongly increased in lymphocytes from chronically infected mice and in vitro limiting dilution analysis confirmed that the vast majority of L. major‐reactive T cells was L3T4Ly‐24. In genetically susceptible mice with chronic cutaneous leishmaniasis, Ly‐24 therefore appears to be a marker for lymphocytes with the capacity to abrogate resistance to disease, these cells being activated and expanding in the course of progressive L. major infection. Ly‐24 expression is a useful tool for phenotypic identification and selective enrichment of antigen‐activated and possibly memory T cells. It may facilitate the isolation of L. major‐specific T cell clones with defined activities.

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Murine cutaneous leishmaniasis : Susceptibility correlates with differential expansion of helper T-cell subsets

Cited by 186 publications

References 16 publications

Dissociation of disease susceptibility, inflammation and cytokine profile in lmr1/2 congenic mice infected with Leishmania major

Dissociation of disease susceptibility, inflammation and cytokine profile in lmr1/2 congenic mice infected with Leishmania major

Leishmaniasis host response loci (lmr1–3) modify disease severity through a Th1/Th2-independent pathway

L3T4 T cells promoting susceptibility to murine cutaneous leishmaniasis express the surface marker Ly‐24 (Pgp‐1)

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