Priming of CD8+ and CD4+ T Cells in Experimental Leishmaniasis Is Initiated by Different Dendritic Cell Subtypes

A differential behavior among infected and bystander dendritic cells (DCs) has been explored in different infection models. We have analyzed both populations sorted on contact with visceral Leishmania infantum on a susceptible mice model evaluating the subsequent repercussions on adaptive immune response. Our results demonstrate a clear dichotomy between the immunomodulatory abilities of bystander and infected DCs. The bystander population presents increased levels of IL-12p40 and costimulatory molecules being capable to induce CD4+ T cell activation with immune protective capabilities. In contrast, infected DCs, which express lower costimulatory molecules and higher levels of IL-10, promote the development of Leishmania Ag-specific, nonprotective T-bet+IFN-γ+IL-10+ CD4+ T cells with an effector phenotype. This specific polarization was found to be dependent on IL-12p70. Splenic infected DCs recovered from chronic infected animals are similarly capable to polarize ex vivo syngeneic naive CD4+ T cells toward a T-bet+IFN-γ+IL-10+ phenotype. Further analysis revealed that only MHC class IIhigh–infected DCs were responsible for this polarization. The adoptive transfer of such polarized CD4+ T cells facilitates visceral leishmaniasis in BALB/c mice in a clear contrast with their counterpart generated with bystander DCs that significantly potentiate protection. Further, we demonstrated that CD4+ T cells primed by infected DCs in an IL-10 free system, thus deprived of T-bet+IFN-γ+IL-10+ population, restore the immune response and reduce parasite load, supporting a deleterious role of IFN-γ+IL-10+ T cells in the maintenance of infection. Overall, our results highlight novel subversion mechanisms by which nonprotective T-bet+IFN-γ+IL-10+ T cells are associated with chronicity and prolonged parasite persistence.

Section: Discussionmentioning

confidence: 99%

Leishmania-Infected MHC Class IIhigh Dendritic Cells Polarize CD4+ T Cells toward a Nonprotective T-bet+ IFN-γ+ IL-10+ Phenotype

Resende

Moreira

Augusto

et al. 2013

“…2 Langerin 2 DCs within draining LNs present L. major Ag to CD4 + T cells (7), whereas Langerin + DCs present Leishmania Ag to CD8 + T cells (8). During the late phase of L. major infections, dermal monocyte-derived DCs (CD11c int Ly6C lo MHC II hi DEC-205 int ) are the major APCs that activate specific CD4 + T cells and are the main source of IL-12 (9).…”

Section: Irf4 In Dendritic Cells Inhibits Il-12 Production and Contromentioning

confidence: 99%

IRF4 in Dendritic Cells Inhibits IL-12 Production and Controls Th1 Immune Responses against Leishmania major

Akbari

Honma

Kimura

et al. 2014

IRF4 is a transcription factor from the IRF factor family that plays pivotal roles in the differentiation and function of T and B lymphocytes. Although IRF4 is also expressed in dendritic cells (DCs) and macrophages, its roles in these cells in vivo are not clearly understood. In this study, conditional knockout mice that lack IRF4 in DCs or macrophages were generated and infected with Leishmania major. Mice lacking DC expression of IRF4 showed reduced footpad swelling compared with C57BL/6 mice, whereas those lacking IRF4 in macrophages did not. Mice with IRF4-deficient DCs also showed reduced parasite burden, and their CD4+ T cells produced higher levels of IFN-γ in response to L. major Ag. In the draining lymph nodes, the proportion of activated CD4+ T cells in these mice was similar to that in the control, but the proportion of IFN-γ–producing cells was increased, suggesting a Th1 bias in the immune response. Moreover, the numbers of migrating Langerhans cells and other migratory DCs in the draining lymph nodes were reduced both before and postinfection in mice with IRF4 defects in DCs, but higher levels of IL-12 were observed in IRF4-deficient DCs. These results imply that IRF4 expression in DCs inhibits their ability to produce IL-12 while promoting their migratory behavior, thus regulating CD4+ T cell responses against local infection with L. major.

“…After ablation, epidermal LC do not reappear until at least 10 d, whereas LdDC start to repopulate the dermis already after ∼3 d. Thus, appropriate timing of ablation regimens facilitated the differential analysis of skin DC subsets. Using this approach, LdDC were identified as exquisite activators of CD8 + T cells in mouse models of contact hypersensitivity (11), leishmaniasis (15), or herpes infection (16). Cross-presentation of skin-borne Ags by CD103 + LdDC was also demonstrated in transgenic mouse models of keratinocyte-restricted expression of membrane-bound OVA (14).…”

mentioning

confidence: 99%

“…Cross-presentation of skin-borne Ags by CD103 + LdDC was also demonstrated in transgenic mouse models of keratinocyte-restricted expression of membrane-bound OVA (14). In contrast to CD8 + T cells, CD4 + T cell activation seems to be independent of a langerin + DC subset (15,16). DNA vaccines, particularly when administered by gene gun technology, have proven highly efficient inducers of CD8 + T cell-mediated immunity, at least in experimental mouse models (17)(18)(19)(20).…”

mentioning

confidence: 99%

Langerin+ Dermal Dendritic Cells Are Critical for CD8+ T Cell Activation and IgH γ-1 Class Switching in Response to Gene Gun Vaccines

Stoecklinger

Eticha

Mesdaghi

et al. 2011

Self Cite

The C-type lectin langerin/CD207 was originally discovered as a specific marker for epidermal Langerhans cells (LC). Recently, additional and distinct subsets of langerin+ dendritic cells (DC) have been identified in lymph nodes and peripheral tissues of mice. Although the role of LC for immune activation or modulation is now being discussed controversially, other langerin+ DC appear crucial for protective immunity in a growing set of infection and vaccination models. In knock-in mice that express the human diphtheria toxin receptor under control of the langerin promoter, injection of diphtheria toxin ablates LC for several weeks whereas other langerin+ DC subsets are replenished within just a few days. Thus, by careful timing of diphtheria toxin injections selective states of deficiency in either LC only or all langerin+ cells can be established. Taking advantage of this system, we found that, unlike selective LC deficiency, ablation of all langerin+ DC abrogated the activation of IFN-γ–producing and cytolytic CD8+ T cells after gene gun vaccination. Moreover, we identified migratory langerin+ dermal DC as the subset that directly activated CD8+ T cells in lymph nodes. Langerin+ DC were also critical for IgG1 but not IgG2a Ab induction, suggesting differential polarization of CD4+ T helper cells by langerin+ or langerin-negative DC, respectively. In contrast, protein vaccines administered with various adjuvants induced IgG1 independently of langerin+ DC. Taken together, these findings reflect a highly specialized division of labor between different DC subsets both with respect to Ag encounter as well as downstream processes of immune activation.