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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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CD8+ T cells are not required for healing a low dose infection if Th2 cell development is blocked. (A) Anti–IL-4 mAb promotes healing in low dose–infected CD8-deficient mice. CD8-deficient mice infected with a low dose of L. major were injected intraperitoneally with 2 mg anti–IL-4 mAb (○) or control rat IgG (▪) at the time of infection and weekly thereafter for 3 wk. Mice were monitored weekly for lesion size and killed at 11 wk to determine parasite burden. (B) Anti–IL-4 mAb treatment blocks the low dose–induced Th2 response. At the time of death, dLN cells were stimulated with SLA and the supernatant fluids were assayed for IFN-γ and IL-4 by ELISA. (C) IL-12 promotes healing in low dose–infected CD8-deficient mice. CD8-deficient mice were infected with a low dose of L. major resuspended in 0.5 μg IL-12. Infected mice received additional injections of 0.5 μg IL-12 or PBS intraperitoneally on days 3 and 6, and lesion size was monitored weekly. 11 wk after infection, mice were killed to estimate parasite burden in the ear. (D) IFN-γ and IL-4 production by dLN cells from IL-12– and PBS-treated mice after in vitro stimulation with SLA. Data presented are a representative of two experiments with similar results.
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fig4: CD8+ T cells are not required for healing a low dose infection if Th2 cell development is blocked. (A) Anti–IL-4 mAb promotes healing in low dose–infected CD8-deficient mice. CD8-deficient mice infected with a low dose of L. major were injected intraperitoneally with 2 mg anti–IL-4 mAb (○) or control rat IgG (▪) at the time of infection and weekly thereafter for 3 wk. Mice were monitored weekly for lesion size and killed at 11 wk to determine parasite burden. (B) Anti–IL-4 mAb treatment blocks the low dose–induced Th2 response. At the time of death, dLN cells were stimulated with SLA and the supernatant fluids were assayed for IFN-γ and IL-4 by ELISA. (C) IL-12 promotes healing in low dose–infected CD8-deficient mice. CD8-deficient mice were infected with a low dose of L. major resuspended in 0.5 μg IL-12. Infected mice received additional injections of 0.5 μg IL-12 or PBS intraperitoneally on days 3 and 6, and lesion size was monitored weekly. 11 wk after infection, mice were killed to estimate parasite burden in the ear. (D) IFN-γ and IL-4 production by dLN cells from IL-12– and PBS-treated mice after in vitro stimulation with SLA. Data presented are a representative of two experiments with similar results.

Mentions: If CD8+ T cells are only necessary to modulate the Th2 response induced by exposure to low doses of antigen, then blocking Th2 cell development by other means should eliminate the requirement for CD8+ T cells. To test this, we treated CD8-deficient mice with either neutralizing anti–IL-4 mAb or IL-12. In contrast to untreated animals, CD8-deficient mice depleted of IL-4 were able to heal their low dose infections with the same kinetics as that seen in B6 mice, and exhibited a reduced parasite burden (Fig. 4 A). The healing response seen in low dose CD8-deficient infected mice that were treated with anti–IL-4 was associated with enhanced IFN-γ responses and decreased IL-4 responses (Fig. 4 B). Similarly, low dose–infected CD8-deficient mice treated with IL-12 failed to develop disease, effectively controlled their parasites, and exhibited a Th1 response (Fig. 4, C and D). Taken together, these results indicate that the conditional requirement for CD8+ T cells in a low dose infection is due to their role in reversing the initial Th2 response and that if this response is blocked, CD8+ T cells are unnecessary for lesion resolution.


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)

CD8+ T cells are not required for healing a low dose infection if Th2 cell development is blocked. (A) Anti–IL-4 mAb promotes healing in low dose–infected CD8-deficient mice. CD8-deficient mice infected with a low dose of L. major were injected intraperitoneally with 2 mg anti–IL-4 mAb (○) or control rat IgG (▪) at the time of infection and weekly thereafter for 3 wk. Mice were monitored weekly for lesion size and killed at 11 wk to determine parasite burden. (B) Anti–IL-4 mAb treatment blocks the low dose–induced Th2 response. At the time of death, dLN cells were stimulated with SLA and the supernatant fluids were assayed for IFN-γ and IL-4 by ELISA. (C) IL-12 promotes healing in low dose–infected CD8-deficient mice. CD8-deficient mice were infected with a low dose of L. major resuspended in 0.5 μg IL-12. Infected mice received additional injections of 0.5 μg IL-12 or PBS intraperitoneally on days 3 and 6, and lesion size was monitored weekly. 11 wk after infection, mice were killed to estimate parasite burden in the ear. (D) IFN-γ and IL-4 production by dLN cells from IL-12– and PBS-treated mice after in vitro stimulation with SLA. Data presented are a representative of two experiments with similar results.
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Related In: Results  -  Collection

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fig4: CD8+ T cells are not required for healing a low dose infection if Th2 cell development is blocked. (A) Anti–IL-4 mAb promotes healing in low dose–infected CD8-deficient mice. CD8-deficient mice infected with a low dose of L. major were injected intraperitoneally with 2 mg anti–IL-4 mAb (○) or control rat IgG (▪) at the time of infection and weekly thereafter for 3 wk. Mice were monitored weekly for lesion size and killed at 11 wk to determine parasite burden. (B) Anti–IL-4 mAb treatment blocks the low dose–induced Th2 response. At the time of death, dLN cells were stimulated with SLA and the supernatant fluids were assayed for IFN-γ and IL-4 by ELISA. (C) IL-12 promotes healing in low dose–infected CD8-deficient mice. CD8-deficient mice were infected with a low dose of L. major resuspended in 0.5 μg IL-12. Infected mice received additional injections of 0.5 μg IL-12 or PBS intraperitoneally on days 3 and 6, and lesion size was monitored weekly. 11 wk after infection, mice were killed to estimate parasite burden in the ear. (D) IFN-γ and IL-4 production by dLN cells from IL-12– and PBS-treated mice after in vitro stimulation with SLA. Data presented are a representative of two experiments with similar results.
Mentions: If CD8+ T cells are only necessary to modulate the Th2 response induced by exposure to low doses of antigen, then blocking Th2 cell development by other means should eliminate the requirement for CD8+ T cells. To test this, we treated CD8-deficient mice with either neutralizing anti–IL-4 mAb or IL-12. In contrast to untreated animals, CD8-deficient mice depleted of IL-4 were able to heal their low dose infections with the same kinetics as that seen in B6 mice, and exhibited a reduced parasite burden (Fig. 4 A). The healing response seen in low dose CD8-deficient infected mice that were treated with anti–IL-4 was associated with enhanced IFN-γ responses and decreased IL-4 responses (Fig. 4 B). Similarly, low dose–infected CD8-deficient mice treated with IL-12 failed to develop disease, effectively controlled their parasites, and exhibited a Th1 response (Fig. 4, C and D). Taken together, these results indicate that the conditional requirement for CD8+ T cells in a low dose infection is due to their role in reversing the initial Th2 response and that if this response is blocked, CD8+ T cells are unnecessary for lesion resolution.

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