Limits...
Leishmania mexicana induces limited recruitment and activation of monocytes and monocyte-derived dendritic cells early during infection.

Petritus PM, Manzoni-de-Almeida D, Gimblet C, Gonzalez Lombana C, Scott P - PLoS Negl Trop Dis (2012)

Bottom Line: Moreover, monocytes that differentiate into mo-DCs in L. mexicana lesions produced less iNOS and migrated less efficiently to the draining lymph node as compared to those from L. major infected mice.Treatment of L. mexicana infected mice with α-IL-10R antibody resulted in increased recruitment of monocytes to the lesion along with greater production of IFN-γ and iNOS.Taken together, these data suggest that during L. mexicana infection reduced recruitment, activation and subsequent migration of monocytes and mo-DCs to the draining lymph nodes may result in the insufficient priming of a Th1 response.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.

ABSTRACT
While C57BL/6 mice infected in the ear with L. major mount a vigorous Th1 response and resolve their lesions, the Th1 response in C57BL/6 mice infected with L. mexicana is more limited, resulting in chronic, non-healing lesions. The aim of this study was to determine if the limited immune response following infection with L. mexicana is related to a deficiency in the ability of monocyte-derived dendritic cells (mo-DCs) to prime a sufficient Th1 response. To address this issue we compared the early immune response following L. mexicana infection with that seen in L. major infected mice. Our data show that fewer monocytes are recruited to the lesions of L. mexicana infected mice as compared to mice infected with L. major. Moreover, monocytes that differentiate into mo-DCs in L. mexicana lesions produced less iNOS and migrated less efficiently to the draining lymph node as compared to those from L. major infected mice. Treatment of L. mexicana infected mice with α-IL-10R antibody resulted in increased recruitment of monocytes to the lesion along with greater production of IFN-γ and iNOS. Additionally, injection of DCs into the ear at the time of infection with L. mexicana also led to a more robust Th1 response. Taken together, these data suggest that during L. mexicana infection reduced recruitment, activation and subsequent migration of monocytes and mo-DCs to the draining lymph nodes may result in the insufficient priming of a Th1 response.

Show MeSH

Related in: MedlinePlus

Fewer transferred monocytes migrate to the dLN during L. mexicana infection compared to L. major.Monocytes enriched from CD45.1 C57BL/6 mice were injected into the ear of CD45.2 C57BL/6 mice that were infected for two weeks with either L. major or L. mexicana. Eighteen hours following injection of the monocytes, ears and dLNs were harvested and processed. (A) Absolute number of transferred monocytes (CD11b+ CD45.1+) in the ear. Cells are previously gated on total, live cells that are singlets. (B) Mean fluorescence intensity (MFI) of Ly6C on transferred cells recovered from the ears of infected mice. Percentage (C) or absolute number (D) of CD45.1+ cells in the dLN. These cells are previously gated on live, singlets that are CD11bhi cells. The results expressed are the mean percentage (± SD for FACS plots) or the mean number of cells (± SE for bar graphs) of 3 mice per group. The results are representative of two experiments. * significantly different (p<0.05) compared to L. major infected mice.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3475671&req=5

pntd-0001858-g005: Fewer transferred monocytes migrate to the dLN during L. mexicana infection compared to L. major.Monocytes enriched from CD45.1 C57BL/6 mice were injected into the ear of CD45.2 C57BL/6 mice that were infected for two weeks with either L. major or L. mexicana. Eighteen hours following injection of the monocytes, ears and dLNs were harvested and processed. (A) Absolute number of transferred monocytes (CD11b+ CD45.1+) in the ear. Cells are previously gated on total, live cells that are singlets. (B) Mean fluorescence intensity (MFI) of Ly6C on transferred cells recovered from the ears of infected mice. Percentage (C) or absolute number (D) of CD45.1+ cells in the dLN. These cells are previously gated on live, singlets that are CD11bhi cells. The results expressed are the mean percentage (± SD for FACS plots) or the mean number of cells (± SE for bar graphs) of 3 mice per group. The results are representative of two experiments. * significantly different (p<0.05) compared to L. major infected mice.

Mentions: We next wanted to determine if the microenvironment within L. mexicana lesions actively inhibited DC migration. Therefore, we injected the same number of CD45 disparate monocytes into L. major or L. mexicana lesions and evaluated their migration to the draining lymph node. Figure 5A shows an equivalent number of CD11b+ CD45.1+ cells in the ear of L. major or L. mexicana infected mice approximately 18 hours following monocyte transfer. Interestingly, the expression of Ly6C on the donor monocytes was lower in L. major infected mice as compared to L. mexicana infected mice (Fig. 5B). As downregulation of Ly6C is associated with activation of mo-DCs [24], [31], these data suggest that mo-DCs in L. mexicana infected mice do not differentiate as efficiently as mo-DCs from L. major infected mice. Even more strikingly, there is a dramatic increase in both the frequency and absolute number of transferred cells in the draining lymph node of L. major infected as compared to L. mexicana infected mice (Fig. 5C and D), indicating that L. mexicana infection does not increase mo-DC trafficking to dLNs. However, we cannot exclude the possibility that there may be a difference in retention in the dLN of L. major versus L. mexicana infected mice. Together, these data indicate that a lack of mo-DCs migration from the site of L. mexicana infection to the draining lymph node may prevent T cell priming and impair lymph node expansion, precluding the induction of a protective Th1 response and resulting in the development of chronic disease.


Leishmania mexicana induces limited recruitment and activation of monocytes and monocyte-derived dendritic cells early during infection.

Petritus PM, Manzoni-de-Almeida D, Gimblet C, Gonzalez Lombana C, Scott P - PLoS Negl Trop Dis (2012)

Fewer transferred monocytes migrate to the dLN during L. mexicana infection compared to L. major.Monocytes enriched from CD45.1 C57BL/6 mice were injected into the ear of CD45.2 C57BL/6 mice that were infected for two weeks with either L. major or L. mexicana. Eighteen hours following injection of the monocytes, ears and dLNs were harvested and processed. (A) Absolute number of transferred monocytes (CD11b+ CD45.1+) in the ear. Cells are previously gated on total, live cells that are singlets. (B) Mean fluorescence intensity (MFI) of Ly6C on transferred cells recovered from the ears of infected mice. Percentage (C) or absolute number (D) of CD45.1+ cells in the dLN. These cells are previously gated on live, singlets that are CD11bhi cells. The results expressed are the mean percentage (± SD for FACS plots) or the mean number of cells (± SE for bar graphs) of 3 mice per group. The results are representative of two experiments. * significantly different (p<0.05) compared to L. major infected mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3475671&req=5

pntd-0001858-g005: Fewer transferred monocytes migrate to the dLN during L. mexicana infection compared to L. major.Monocytes enriched from CD45.1 C57BL/6 mice were injected into the ear of CD45.2 C57BL/6 mice that were infected for two weeks with either L. major or L. mexicana. Eighteen hours following injection of the monocytes, ears and dLNs were harvested and processed. (A) Absolute number of transferred monocytes (CD11b+ CD45.1+) in the ear. Cells are previously gated on total, live cells that are singlets. (B) Mean fluorescence intensity (MFI) of Ly6C on transferred cells recovered from the ears of infected mice. Percentage (C) or absolute number (D) of CD45.1+ cells in the dLN. These cells are previously gated on live, singlets that are CD11bhi cells. The results expressed are the mean percentage (± SD for FACS plots) or the mean number of cells (± SE for bar graphs) of 3 mice per group. The results are representative of two experiments. * significantly different (p<0.05) compared to L. major infected mice.
Mentions: We next wanted to determine if the microenvironment within L. mexicana lesions actively inhibited DC migration. Therefore, we injected the same number of CD45 disparate monocytes into L. major or L. mexicana lesions and evaluated their migration to the draining lymph node. Figure 5A shows an equivalent number of CD11b+ CD45.1+ cells in the ear of L. major or L. mexicana infected mice approximately 18 hours following monocyte transfer. Interestingly, the expression of Ly6C on the donor monocytes was lower in L. major infected mice as compared to L. mexicana infected mice (Fig. 5B). As downregulation of Ly6C is associated with activation of mo-DCs [24], [31], these data suggest that mo-DCs in L. mexicana infected mice do not differentiate as efficiently as mo-DCs from L. major infected mice. Even more strikingly, there is a dramatic increase in both the frequency and absolute number of transferred cells in the draining lymph node of L. major infected as compared to L. mexicana infected mice (Fig. 5C and D), indicating that L. mexicana infection does not increase mo-DC trafficking to dLNs. However, we cannot exclude the possibility that there may be a difference in retention in the dLN of L. major versus L. mexicana infected mice. Together, these data indicate that a lack of mo-DCs migration from the site of L. mexicana infection to the draining lymph node may prevent T cell priming and impair lymph node expansion, precluding the induction of a protective Th1 response and resulting in the development of chronic disease.

Bottom Line: Moreover, monocytes that differentiate into mo-DCs in L. mexicana lesions produced less iNOS and migrated less efficiently to the draining lymph node as compared to those from L. major infected mice.Treatment of L. mexicana infected mice with α-IL-10R antibody resulted in increased recruitment of monocytes to the lesion along with greater production of IFN-γ and iNOS.Taken together, these data suggest that during L. mexicana infection reduced recruitment, activation and subsequent migration of monocytes and mo-DCs to the draining lymph nodes may result in the insufficient priming of a Th1 response.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.

ABSTRACT
While C57BL/6 mice infected in the ear with L. major mount a vigorous Th1 response and resolve their lesions, the Th1 response in C57BL/6 mice infected with L. mexicana is more limited, resulting in chronic, non-healing lesions. The aim of this study was to determine if the limited immune response following infection with L. mexicana is related to a deficiency in the ability of monocyte-derived dendritic cells (mo-DCs) to prime a sufficient Th1 response. To address this issue we compared the early immune response following L. mexicana infection with that seen in L. major infected mice. Our data show that fewer monocytes are recruited to the lesions of L. mexicana infected mice as compared to mice infected with L. major. Moreover, monocytes that differentiate into mo-DCs in L. mexicana lesions produced less iNOS and migrated less efficiently to the draining lymph node as compared to those from L. major infected mice. Treatment of L. mexicana infected mice with α-IL-10R antibody resulted in increased recruitment of monocytes to the lesion along with greater production of IFN-γ and iNOS. Additionally, injection of DCs into the ear at the time of infection with L. mexicana also led to a more robust Th1 response. Taken together, these data suggest that during L. mexicana infection reduced recruitment, activation and subsequent migration of monocytes and mo-DCs to the draining lymph nodes may result in the insufficient priming of a Th1 response.

Show MeSH
Related in: MedlinePlus