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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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Leishmanial antigen overcomes the dependence on CD8+ T cells for resolution of low dose infections. CD8-deficient mice infected with a low dose, a high dose, or a low dose of L. major suspended in 106 freeze-thaw parasites (low dose plus antigen) were killed at 3 wk and the dLN cells were labeled with CFSE, stimulated with SLA for 5 d, and stained for intracellular IFN-γ. Proliferation (A) and intracellular IFN-γ secretion (B) by CD4+ T cells from infected mice. (C) Some cells were stimulated with SLA for 72 h and the supernatant fluids were collected and assayed for IFN-γ and IL-4 production by ELISA. (D) Enhanced resistance in CD8-deficient mice infected with low dose L. major mixed with leishmanial antigen. CD8-deficient mice were infected with a low dose of L. major or a low dose given with leishmanial antigen as described above, and lesion size was measured weekly. Some low dose–infected B6 (WT) mice were included as positive control. Data presented are a representative of two experiments with similar results.
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fig3: Leishmanial antigen overcomes the dependence on CD8+ T cells for resolution of low dose infections. CD8-deficient mice infected with a low dose, a high dose, or a low dose of L. major suspended in 106 freeze-thaw parasites (low dose plus antigen) were killed at 3 wk and the dLN cells were labeled with CFSE, stimulated with SLA for 5 d, and stained for intracellular IFN-γ. Proliferation (A) and intracellular IFN-γ secretion (B) by CD4+ T cells from infected mice. (C) Some cells were stimulated with SLA for 72 h and the supernatant fluids were collected and assayed for IFN-γ and IL-4 production by ELISA. (D) Enhanced resistance in CD8-deficient mice infected with low dose L. major mixed with leishmanial antigen. CD8-deficient mice were infected with a low dose of L. major or a low dose given with leishmanial antigen as described above, and lesion size was measured weekly. Some low dose–infected B6 (WT) mice were included as positive control. Data presented are a representative of two experiments with similar results.

Mentions: To determine if simply increasing the antigen dose rather than increasing the number of live parasites could promote a Th1 response, we characterized the CD4+ T cell response of B6 and CD8-deficient mice infected with a low dose of live parasites mixed with a high dose of leishmanial antigen. Because similar results were obtained from both mice, only data from CD8-deficient mice are presented. After administration of high doses of antigen in the form of killed parasites, CD4+ T cell proliferation, and the percent of those cells producing IFN-γ, was equivalent to that seen with a high dose of live L. major (Fig. 3, A and B). Similarly, IFN-γ and IL-4 production analyzed by ELISA indicated that high antigen doses promoted a Th1 response (Fig. 3 C), suggesting that the critical factor in CD4+ T cell activation is the dose of antigen and not whether the parasites are alive.


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)

Leishmanial antigen overcomes the dependence on CD8+ T cells for resolution of low dose infections. CD8-deficient mice infected with a low dose, a high dose, or a low dose of L. major suspended in 106 freeze-thaw parasites (low dose plus antigen) were killed at 3 wk and the dLN cells were labeled with CFSE, stimulated with SLA for 5 d, and stained for intracellular IFN-γ. Proliferation (A) and intracellular IFN-γ secretion (B) by CD4+ T cells from infected mice. (C) Some cells were stimulated with SLA for 72 h and the supernatant fluids were collected and assayed for IFN-γ and IL-4 production by ELISA. (D) Enhanced resistance in CD8-deficient mice infected with low dose L. major mixed with leishmanial antigen. CD8-deficient mice were infected with a low dose of L. major or a low dose given with leishmanial antigen as described above, and lesion size was measured weekly. Some low dose–infected B6 (WT) mice were included as positive control. 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

fig3: Leishmanial antigen overcomes the dependence on CD8+ T cells for resolution of low dose infections. CD8-deficient mice infected with a low dose, a high dose, or a low dose of L. major suspended in 106 freeze-thaw parasites (low dose plus antigen) were killed at 3 wk and the dLN cells were labeled with CFSE, stimulated with SLA for 5 d, and stained for intracellular IFN-γ. Proliferation (A) and intracellular IFN-γ secretion (B) by CD4+ T cells from infected mice. (C) Some cells were stimulated with SLA for 72 h and the supernatant fluids were collected and assayed for IFN-γ and IL-4 production by ELISA. (D) Enhanced resistance in CD8-deficient mice infected with low dose L. major mixed with leishmanial antigen. CD8-deficient mice were infected with a low dose of L. major or a low dose given with leishmanial antigen as described above, and lesion size was measured weekly. Some low dose–infected B6 (WT) mice were included as positive control. Data presented are a representative of two experiments with similar results.
Mentions: To determine if simply increasing the antigen dose rather than increasing the number of live parasites could promote a Th1 response, we characterized the CD4+ T cell response of B6 and CD8-deficient mice infected with a low dose of live parasites mixed with a high dose of leishmanial antigen. Because similar results were obtained from both mice, only data from CD8-deficient mice are presented. After administration of high doses of antigen in the form of killed parasites, CD4+ T cell proliferation, and the percent of those cells producing IFN-γ, was equivalent to that seen with a high dose of live L. major (Fig. 3, A and B). Similarly, IFN-γ and IL-4 production analyzed by ELISA indicated that high antigen doses promoted a Th1 response (Fig. 3 C), suggesting that the critical factor in CD4+ T cell activation is the dose of antigen and not whether the parasites are alive.

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