LNSCs present peptide–MHCII complexes acquired from DCs to CD4+ T cells and induce T cell dysfunction by preventing their proliferation and survival.

Human infection with Leishmania braziliensis leads to the establishment of cutaneous leishmaniasis (CL), characterized by the appearance of skin lesions that progress from nonulcerated to ulcerated forms. Our goal was to characterize the immunological kinetics associated with this progression, comparing the cellular composition, cytokines and granzyme expression between lesions of patients with early (E-CL) and late stages (L-CL) of CL. Histopathological analysis showed that lesions from L-CL had more exuberant inflammatory infiltrate as compared to E-CL. Although E-CL and L-CL lesions were predominantly mononuclear, lesions from E-CL patients presented higher neutrophil and eosinophil counts than L-CL. While percentages of CD4+ and of CD68+ cells were slightly higher in L-CL, a five-fold increase of CD8+ cells was observed in L-CL, as compared to E-CL. Moreover, CD8+ T-cells from L-CL expressed significantly higher levels of granzymeA than E-CL. Interestingly, granzymeA expression was positively correlated with intensity of the inflammatory infiltrate in L-CL but not E-CL. Lastly, percentages of IFN-γ + and IL-10+ cells were higher in L-CL as compared to E-CL, with CD4+ T-cells and CD68+ monocytes as the main sources of these cytokines, respectively. These results suggest that recruitment of CD8+granzymeA+ T-cells is involved in lesion progression in human CL.

MHCII-restricted antigen presentation by lymph node stromal cells is essential for regulatory T-cell proliferation and functions, and for the regulation of autoimmunity.

Plasmacytoid dendritic cells (pDCs) have been shown to both mediate and prevent autoimmunity, and the regulation of their immunogenic versus tolerogenic functions remains incompletely understood. Here we demonstrate that, compared to other cells, pDCs are the major expressors of Indoleamine-2,3-dioxygenase (IDO) in steady-state lymph nodes (LNs). IDO expression by LN pDCs was closely dependent on MHCII-mediated, antigen-dependent, interactions with Treg. We further established that IDO production by pDCs was necessary to confer suppressive function to Tregs. During EAE development, IDO expression by pDCs was required for the generation of Tregs capable of dampening the priming of encephalitogenic T cell and disease severity. Thus, we describe a novel crosstalk between pDCs and Tregs: Tregs shape tolerogenic functions of pDCs prior to inflammation, such that pDCs in turn, promote Treg suppressive functions during autoimmunity.

Lymphatic endothelial cells (LECs) chemoattract naïve T cells and promote their survival in the lymph nodes, and can cross-present antigens to naïve CD8 + T cells to drive their proliferation despite lacking key costimulatory molecules. However, the functional consequence of LEC priming of CD8 + T cells is unknown. Here, we show that while many proliferating LECeducated T cells enter early apoptosis, the remainders comprise a long-lived memory subset, with transcriptional, metabolic, and phenotypic features of central memory and stem cell-like memory T cells. In vivo, these memory cells preferentially home to lymph nodes and display rapid proliferation and effector differentiation following memory recall, and can protect mice against a subsequent bacterial infection. These findings introduce a new immunomodulatory role for LECs in directly generating a memory-like subset of quiescent yet antigenexperienced CD8 + T cells that are long-lived and can rapidly differentiate into effector cells upon inflammatory antigenic challenge.

To investigate the role of Toll-like receptor 9 (TLR9) in innate immunity to Mycobacterium avium, TLR9, TLR2, and MyD88 knockout (KO) mice were infected with this bacterium. Bacterial burdens were higher in the spleens, livers, and lungs of infected TLR9 KO mice than in those of C57BL/6 mice, indicating that TLR9 is required for efficient control of M. avium infection. However, TLR9 KO or TLR2 KO spleen cells displayed normal M. avium-induced tumor necrosis factor alpha (TNF-␣) and gamma interferon (IFN-␥) responses. This finding was confirmed by determining the number of splenic CD4؉ T cells producing IFN-␥ by flow cytometry. Furthermore, TLR2 and MyD88, but not TLR9, played a major role in interleukin-12 and TNF-␣ production by M. avium-infected macrophages and dendritic cells (DCs). We also found that major histocompatibility complex class II molecule expression on DCs is regulated by TLR2 and MyD88 signaling but not by TLR9. Finally, lack of TLR9, TLR2, or MyD88 reduced the numbers of macrophages, epithelioid cells, and lymphocytes in M. avium-induced granulomas but only MyD88 deficiency affected the number of liver granulomas. In summary, our data demonstrated that the involvement of TLR9 in the control of M. avium infection is not related to the induction of Th1 responses.Mycobacterium avium is an opportunistic pathogen that infects mostly immunocompromised individuals (15). After entering the host, mycobacteria are internalized by macrophages and survive host killing by preventing phagolysosome fusion, inhibiting the acidification of the phagocytic vacuole, and disrupting the actin cytoskeleton of the cell (1). Similarly to infection with Mycobacterium tuberculosis, the interaction of M. avium with phagocytic cells results in the recruitment of CD4 ϩ T lymphocytes and in the secretion of gamma interferon (IFN-␥) and other proinflammatory cytokines (5). This process is suggested to be at least partially dependent on the recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) expressed on innate immunity cells, which in turn leads to MyD88-mediated activation of the cytokine geneassociated transcription factor 20,24).The involvement of TLRs in host resistance to M. avium was suspected given the greatly augmented susceptibility of MyD88-deficient mice to infection with this bacterium (6, 10). Even though TLR2 has been proposed to be a major receptor for the recognition of glycopeptidolipids from M. avium (28), TLR2 knockout (KO) mice were found to be less susceptible to M. avium infection than MyD88 KO mice. Additionally, it has been reported that TLR4 deficiency does not affect the resistance of mice to M. avium (6). Therefore, these findings suggest that, in addition to TLR2, host control of M. avium infection involves other, as-yet-undefined, MyD88-dependent members of the interleukin-1 (IL-1)/TLR superfamily.In the present study, we investigated the role of TLR9 in innate immune recognition of M. avium, since this receptor localizes to the endosomes and phagolysosomes, where i...

Plasmacytoid dendritic cells (pDCs) exhibit both innate and adaptive functions. In particular they are the main source of type I IFNs and directly impact T cell responses through antigen presentation. We have previously demonstrated that during experimental autoimmune encephalomyelitis (EAE) initiation, myelin-antigen presentation by pDCs is associated with suppressive Treg development and results in attenuated EAE. Here, we show that pDCs transferred during acute disease phase confer recovery from EAE. Clinical improvement is associated with migration of injected pDCs into inflamed CNS and is dependent on the subsequent and selective chemerin-mediated recruitment of endogenous pDCs to the CNS. The protective effect requires pDC pre-loading with myelin antigen, and is associated with the modulation of CNS-infiltrating pDC phenotype and inhibition of CNS encephalitogenic T cells. This study may pave the way for novel pDC-based cell therapies in autoimmune diseases, aiming at specifically modulating pathogenic cells that induce and sustain autoimmune inflammation.

Schistosoma mansoni schistosomula are the most susceptible parasite life stage to host immune system attack. Complex host-parasite interactions take place on Schistosoma tegument, which is a unique double membrane structure involved in nutrition and immune evasion. Herein, we have demonstrated that schistosomula tegument (Smteg) activates Dendritic cells to produce IL-12p40, TNF-alpha and also to up-regulate the co-stimulatory molecules CD40 and CD86. Moreover, using DCs derived from MyD88-, TLR2-, TLR4- and TLR9-deficient mice we have shown that the ability of Smteg to activate DCs to produce IL-12 and TNF-alpha involves TLR4/Smteg interaction and MyD88 signaling pathway. Finally, our findings lead us to conclude that TLR4 is a key receptor involved in Smteg induction of pro-inflammatory cytokines.