Antigen presentation by dendritic cells and their instruction of CD4+ T helper cell responses

Dendritic cells are powerful antigen-presenting cells that are essential for the priming of T cell responses.In addition to providing T-cell-receptor ligands and co-stimulatory molecules for naive T cell activation and expansion,dendritic cells are thought to also provide signals for the differentiation of CD4+T cells into effector T cell populations.The mechanisms by which dendritic cells are able to adapt and respond to the great variety of infectious stimuli they are confronted with,and prime an appropriate CD4+T cell response,are only partly understood.It is known that in the steady-state dendritic cells are highly heterogenous both in phenotype and transcriptional profile,and that this variability is dependent on developmental lineage,maturation stage,and the tissue environment in which dendritic cells are located.Exposure to infectious agents interfaces with this pre-existing heterogeneity by providing ligands for pattern-recognition and toll-like receptors that are variably expressed on different dendritic cell subsets,and elicit production of cytokines and chemokines to support innate cell activation and drive T cell differentiation.Here we review current information on dendritic cell biology,their heterogeneity,and the properties of different dendritic cell subsets.We then consider the signals required for the development of different types of Th immune responses,and the cellular and molecular evidence implicating different subsets of dendritic cells in providing such signals.We outline how dendritic cell subsets tailor their response according to the infectious agent,and how such transcriptional plasticity enables them to drive different types of immune responses.

T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

The molecular pathways contributing to humoral-mediated allograft rejection are poorly defined. In this study, we assessed the role of the herpesvirus entry mediator/B- and T-lymphocyte attenuator （HVEM/BTLA） signalling pathway in the context of antibody-mediated allograft rejection. An experimental setting was designed to elucidate whether the blockade of HVEM/BTLA interactions could modulate de novo induction of host antidonor-specific antibodies during the course of graft rejection. To test this hypothesis, fully allogeneic major histocompatibility complex-mismatched skin grafts were transplanted onto the right flank of recipient mice that were treated with isotype control, anti-CD40L or modulatory antibodies of the HVEM/BTLA signalling pathway. The frequencies of CD4 T follicular helper （Tfh） cells （B220-, CD4＋ CXCR5＋ PD-lhigh）, extrafollicular helper cells （B220-, CD4＋ CXCR5- PD-1＋ and PD-1-） and germinal centre （GC） B cells （B220＋Fas＋ GL7＋） were analysed by flow cytometry in draining and non-draining lymph nodes at day 10 post transplantation during the acute phase of graft rejection. The host antidonor isotype-specific humoral immune response was also assessed. Whereas blockade of the CD40/CD40L pathway was highly effective in preventing the allogeneic humoral immune response, antibody-mediated blockade of the HVEM/BTLA-interacting pathway affected neither the expansion of Tfh cells nor the expansion of GC B cells. Consequently, the course of the host antidonor antibody-mediated response proceeded normally, without detectable evidence of impaired development. In summary, these data indicate that HVEM/BTLA interactions are dispensable for the formation of de novo host antidonor isotype-specific antibodies in transplantation.

HVEM,a cosignaling molecular switch,and its interactions with BTLA,CD160 and LIGHT

Temporal and spatial expression of cosignaling receptors and their ligands regulates the early stages of T-cell activation(signal 1,T-cell receptor(TCR)signaling and signal 2,costimulation/coinhibition),clonal expansion and T-cell survival during their differentiation towards effector T cells.Once the inflammatory stimulus is eliminated,effector T cells return to homeostasis after undergoing a contraction phase by activation-induced cell death and the intervention of ligands for coinhibitory receptors,leaving a population of long-term memory T cells.The expression of ligands for coinhibitory receptors on hematopoietic cells and,more importantly,on non-hematopoietic cells of peripheral tissues is a key process in tuning the functional activity of effector T cells to prevent excess tissue inflammation that may lead to immunopathology and subsequent tissue dysfunction.

Innate recognition of Toxoplasma gondii in humans involves a mechanism distinct from that utilized by rodents

Toxoplasma gondii is an intracellular protozoan parasite that infects rodents as part of its natural transmission cycle and induces disease in humans, an end-stage host. As one of the natural hosts of T. gondii, the mouse has been used extensively for elucidating the cellular and molecular basis of immunity to this pathogen while relatively few studies have focused on the response of humans. In our recent work, we identified CD16^＋ monocytes and DC1 dendritic cells as the major myeloid cell populations that respond to T. gondii in human peripheral blood. Interestingly, these myeloid subsets represent the opposite counterparts from those triggered by the parasite in mice. Moreover, whereas the innate cytokine response to T. gondii in the mouse involves stimulation of Toll-like receptors by a soluble parasite ligand, the response of human cells instead requires phagocytosis of the live pathogen. We speculate that these marked distinctions in the pathways utilized for innate recognition of toxoplasma in mouse and man reflect the differing roles of the two hosts in the biology of this parasite.

Correction to: T follicular helper expansion and humoralmediated rejection are independent of the HVEM/BTLA pathway

In this article,one of the grating agencies requested us to incorporate the information,Spanish Government and co-funded by European Union ERDF/ESF,“Investing in your future”,in the acknowledgments section.The correct acknowledgement is as follows:“This work has been supported by grants of the Spanish Ministry of Health(Fondo de Investigaciones Sanitarias,PI13/00029,Spanish Government and co-funded by European Union ERDF/ESF,“Investing in your future”),Department of Education of Castilla and Leon Regional Government(Grant#LE093U13)and Mutua Madrileña Foundation(Basic research grants 2012)to J.I.R.B.;by Miguel Servet National Program(Ministry of National Health)CP12/03063 and by Gerencia Regional de Salud GRS963/A/2014 to M.L.R.G.We are particularly grateful to Mr.Leonides Alaiz for outstanding animal husbandry.”The authors regret the errors.