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Low dose Leishmania major promotes a transient T helper cell type 2 response that is down-regulated by interferon gamma-producing CD8+ T cells.

Uzonna JE, Joyce KL, Scott P - J. Exp. Med. (2004)

Bottom Line: An unresolved issue in the field of T helper (Th) cell development relates to the findings that low doses of antigen promote Th2 cell development in vitro, whereas several classic in vivo studies suggest the opposite.In the absence of CD8+ T cells, the Th2 response was maintained.Thus, the discrepant results seen between in vivo and in vitro studies on the effects of antigen dose on Th cell differentiation may depend upon whether CD8+ T cells participate in the immune response.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia 19104, USA.

ABSTRACT
An unresolved issue in the field of T helper (Th) cell development relates to the findings that low doses of antigen promote Th2 cell development in vitro, whereas several classic in vivo studies suggest the opposite. Here we resolve this paradox by studying the early immune response in mice after infection with different doses of Leishmania major. We found that low parasite doses induced a Th2 response in C57BL/6 (B6) mice, whereas high doses induced a Th1 response. However, the Th2 response in low dose-infected mice was transient and the animals healed. The appearance of a Th1 response after low dose infection was dependent upon the concomitant activation of interferon gamma-producing CD8+ T cells. In the absence of CD8+ T cells, the Th2 response was maintained. However, either neutralization of interleukin (IL)-4 or administration of IL-12 promoted a Th1 response after low dose infection of CD8-deficient mice, indicating that the required role for CD8+ T cells was limited to modulation of CD4+ T cell responses. Thus, the discrepant results seen between in vivo and in vitro studies on the effects of antigen dose on Th cell differentiation may depend upon whether CD8+ T cells participate in the immune response.

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The protective effect of CD8+ T cells is mediated by IFN-γ. (A) CD8-deficient mice were given PBS (CD8 KO) or 107 purified CD8+ T cells from B6 (& WT) or IFN-γ–deficient (& γ-KO) mice, and infected with a low dose of L. major the next day. The course of lesion progression was monitored and 14 wk after infection mice were killed to determine parasite burden. (B) CD8+ T cells from WT, but not IFN-γ–deficient, mice inhibit the low dose–induced Th2 response. At the time of death, dLN cells were stimulated with SLA for 72 h and the supernatant fluids were assayed for IFN-γ and IL-4 production by ELISA. Data presented are a representative of two experiments with similar results.
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fig5: The protective effect of CD8+ T cells is mediated by IFN-γ. (A) CD8-deficient mice were given PBS (CD8 KO) or 107 purified CD8+ T cells from B6 (& WT) or IFN-γ–deficient (& γ-KO) mice, and infected with a low dose of L. major the next day. The course of lesion progression was monitored and 14 wk after infection mice were killed to determine parasite burden. (B) CD8+ T cells from WT, but not IFN-γ–deficient, mice inhibit the low dose–induced Th2 response. At the time of death, dLN cells were stimulated with SLA for 72 h and the supernatant fluids were assayed for IFN-γ and IL-4 production by ELISA. Data presented are a representative of two experiments with similar results.

Mentions: The data above suggests that CD8+ T cells are required for down-regulating the initial Th2 response by proliferating and producing IFN-γ, although it is possible that other IFN-γ–independent mechanisms might be involved. To directly address this, we adoptively transferred CD8+ T cells from B6 or IFN-γ–deficient mice into CD8-deficient mice and infected them with a low dose of L. major. As expected, recipients of WT CD8+ T cells resolved their lesions and efficiently controlled parasite replication. In contrast, mice that received cells from IFN-γ–deficient mice developed progressive disease similar to PBS controls (Fig. 5 A). Corresponding with the outcome of infection, adoptive transfer of WT CD8+ T cells promoted the development of a Th1 response, whereas mice that received IFN-γ–deficient CD8+ T cells exhibited cytokine levels similar to unreconstituted CD8-deficient mice (Fig. 5 B). These data demonstrate that the protective effect of CD8+ T cells during low dose infections is mediated by their production of IFN-γ, which down-regulates the initial Th2 response and enhances Th1 cell development.


Low dose Leishmania major promotes a transient T helper cell type 2 response that is down-regulated by interferon gamma-producing CD8+ T cells.

Uzonna JE, Joyce KL, Scott P - J. Exp. Med. (2004)

The protective effect of CD8+ T cells is mediated by IFN-γ. (A) CD8-deficient mice were given PBS (CD8 KO) or 107 purified CD8+ T cells from B6 (& WT) or IFN-γ–deficient (& γ-KO) mice, and infected with a low dose of L. major the next day. The course of lesion progression was monitored and 14 wk after infection mice were killed to determine parasite burden. (B) CD8+ T cells from WT, but not IFN-γ–deficient, mice inhibit the low dose–induced Th2 response. At the time of death, dLN cells were stimulated with SLA for 72 h and the supernatant fluids were assayed for IFN-γ and IL-4 production by ELISA. Data presented are a representative of two experiments with similar results.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211781&req=5

fig5: The protective effect of CD8+ T cells is mediated by IFN-γ. (A) CD8-deficient mice were given PBS (CD8 KO) or 107 purified CD8+ T cells from B6 (& WT) or IFN-γ–deficient (& γ-KO) mice, and infected with a low dose of L. major the next day. The course of lesion progression was monitored and 14 wk after infection mice were killed to determine parasite burden. (B) CD8+ T cells from WT, but not IFN-γ–deficient, mice inhibit the low dose–induced Th2 response. At the time of death, dLN cells were stimulated with SLA for 72 h and the supernatant fluids were assayed for IFN-γ and IL-4 production by ELISA. Data presented are a representative of two experiments with similar results.
Mentions: The data above suggests that CD8+ T cells are required for down-regulating the initial Th2 response by proliferating and producing IFN-γ, although it is possible that other IFN-γ–independent mechanisms might be involved. To directly address this, we adoptively transferred CD8+ T cells from B6 or IFN-γ–deficient mice into CD8-deficient mice and infected them with a low dose of L. major. As expected, recipients of WT CD8+ T cells resolved their lesions and efficiently controlled parasite replication. In contrast, mice that received cells from IFN-γ–deficient mice developed progressive disease similar to PBS controls (Fig. 5 A). Corresponding with the outcome of infection, adoptive transfer of WT CD8+ T cells promoted the development of a Th1 response, whereas mice that received IFN-γ–deficient CD8+ T cells exhibited cytokine levels similar to unreconstituted CD8-deficient mice (Fig. 5 B). These data demonstrate that the protective effect of CD8+ T cells during low dose infections is mediated by their production of IFN-γ, which down-regulates the initial Th2 response and enhances Th1 cell development.

Bottom Line: An unresolved issue in the field of T helper (Th) cell development relates to the findings that low doses of antigen promote Th2 cell development in vitro, whereas several classic in vivo studies suggest the opposite.In the absence of CD8+ T cells, the Th2 response was maintained.Thus, the discrepant results seen between in vivo and in vitro studies on the effects of antigen dose on Th cell differentiation may depend upon whether CD8+ T cells participate in the immune response.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia 19104, USA.

ABSTRACT
An unresolved issue in the field of T helper (Th) cell development relates to the findings that low doses of antigen promote Th2 cell development in vitro, whereas several classic in vivo studies suggest the opposite. Here we resolve this paradox by studying the early immune response in mice after infection with different doses of Leishmania major. We found that low parasite doses induced a Th2 response in C57BL/6 (B6) mice, whereas high doses induced a Th1 response. However, the Th2 response in low dose-infected mice was transient and the animals healed. The appearance of a Th1 response after low dose infection was dependent upon the concomitant activation of interferon gamma-producing CD8+ T cells. In the absence of CD8+ T cells, the Th2 response was maintained. However, either neutralization of interleukin (IL)-4 or administration of IL-12 promoted a Th1 response after low dose infection of CD8-deficient mice, indicating that the required role for CD8+ T cells was limited to modulation of CD4+ T cell responses. Thus, the discrepant results seen between in vivo and in vitro studies on the effects of antigen dose on Th cell differentiation may depend upon whether CD8+ T cells participate in the immune response.

Show MeSH
Related in: MedlinePlus