Limits...
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.

Show MeSH

Related in: MedlinePlus

CD8+ T cells are not required to control a low dose infection in immune mice. B6 (WT) and CD8-deficient (KO) mice (five mice per group) were infected with 106 (high dose) L. major and allowed to heal. 6 mo after primary infection, healed mice together with some naive controls (five mice each) were challenged with 103 L. major and the course of lesion progression was monitored. 10 wk after challenge mice were killed to estimate parasite burden. Data presented are a representative of two experiments with similar results.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2211781&req=5

fig6: CD8+ T cells are not required to control a low dose infection in immune mice. B6 (WT) and CD8-deficient (KO) mice (five mice per group) were infected with 106 (high dose) L. major and allowed to heal. 6 mo after primary infection, healed mice together with some naive controls (five mice each) were challenged with 103 L. major and the course of lesion progression was monitored. 10 wk after challenge mice were killed to estimate parasite burden. Data presented are a representative of two experiments with similar results.

Mentions: The observation that CD8+ T cells are required for resistance against low dose L. major infection has implications for vaccination strategies against leishmaniasis. Natural infections are initiated by inoculation of low numbers of parasites by the sandfly, which raises the question whether a vaccine targeting CD4+ T cells would be sufficient to mediate resistance to L. major. Indeed, several vaccine studies have found that CD8+ T cells are important for optimal resistance to L. major (22–24). However, whether CD8+ T cells are an obligatory requirement or are necessary due to suboptimal CD4+ T cell induction is unclear. To address this issue, we asked whether CD8-deficient mice that controlled a high dose L. major infection could mount a protective secondary response to low dose challenge. Therefore, B6 and CD8-deficient mice were infected with a high dose of L. major. 6 mo after the primary infection, these healed mice and their age-matched naive controls were challenged with a low dose of L. major. As expected, naive CD8-deficient mice challenged with low dose L. major developed progressive disease, whereas naive B6 mice developed small lesions that eventually resolved. In contrast, both healed B6 and CD8-deficient mice developed minimal lesions after challenge and the lesions contained few parasites (Fig. 6). These results indicate that if sufficient CD4+ T cell immunity is generated, its efficacy and durability are independent of CD8+ T cells. However, whether this only applies to mice that maintain persistent parasites, which would be the case here, has yet to be tested.


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 to control a low dose infection in immune mice. B6 (WT) and CD8-deficient (KO) mice (five mice per group) were infected with 106 (high dose) L. major and allowed to heal. 6 mo after primary infection, healed mice together with some naive controls (five mice each) were challenged with 103 L. major and the course of lesion progression was monitored. 10 wk after challenge mice were killed to estimate parasite burden. 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

fig6: CD8+ T cells are not required to control a low dose infection in immune mice. B6 (WT) and CD8-deficient (KO) mice (five mice per group) were infected with 106 (high dose) L. major and allowed to heal. 6 mo after primary infection, healed mice together with some naive controls (five mice each) were challenged with 103 L. major and the course of lesion progression was monitored. 10 wk after challenge mice were killed to estimate parasite burden. Data presented are a representative of two experiments with similar results.
Mentions: The observation that CD8+ T cells are required for resistance against low dose L. major infection has implications for vaccination strategies against leishmaniasis. Natural infections are initiated by inoculation of low numbers of parasites by the sandfly, which raises the question whether a vaccine targeting CD4+ T cells would be sufficient to mediate resistance to L. major. Indeed, several vaccine studies have found that CD8+ T cells are important for optimal resistance to L. major (22–24). However, whether CD8+ T cells are an obligatory requirement or are necessary due to suboptimal CD4+ T cell induction is unclear. To address this issue, we asked whether CD8-deficient mice that controlled a high dose L. major infection could mount a protective secondary response to low dose challenge. Therefore, B6 and CD8-deficient mice were infected with a high dose of L. major. 6 mo after the primary infection, these healed mice and their age-matched naive controls were challenged with a low dose of L. major. As expected, naive CD8-deficient mice challenged with low dose L. major developed progressive disease, whereas naive B6 mice developed small lesions that eventually resolved. In contrast, both healed B6 and CD8-deficient mice developed minimal lesions after challenge and the lesions contained few parasites (Fig. 6). These results indicate that if sufficient CD4+ T cell immunity is generated, its efficacy and durability are independent of CD8+ T cells. However, whether this only applies to mice that maintain persistent parasites, which would be the case here, has yet to be tested.

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