Immunological decision‐making: how does the immune system decide to mount a helper T‐cell response?

Kaiko, Gerard E.; Horvat, Jay C.; Beagley, Kenneth W.; Hansbro, Philip M.

doi:10.1111/j.1365-2567.2007.02719.x

Cited by 569 publications

(447 citation statements)

References 103 publications

(226 reference statements)

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“…Amongst the many observed phenotypes of CD4 1 T cells, their division into Th1 and Th2 cells that secrete predominantly IFN-g and IL-4 respectively, remains an important one, and their generation is dependent mainly on cytokine environment [18]. Another CD4 1 phenotype, the Treg, can act by engagement of CTLA-4, or through secretion of inhibitory cytokines such as IL-10 or TGF-b, and their action is important for dampening excessive immune responses in malaria [3].…”

Section: Introductionmentioning

confidence: 99%

Multiple functions of human T cells generated by experimental malaria challenge

et al. 2009

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Protective immunity generated following malaria infection may be comprised of Ab or T cells against malaria Ag of different stages; however, the short-lived immunity that is observed suggests deficiency in immune memory or regulatory activity. In this study, cellular immune responses were investigated in individuals receiving Plasmodium falciparum sporozoite challenge by the natural (mosquito bite) route as part of a malaria vaccine efficacy trial. Parasitemia, monitored by blood film microscopy and PCR, was subsequently cleared with drugs. All individuals demonstrated stable IFN-c, IL-2 and IL-4 ex vivo ELISPOT effector responses against P. falciparum-infected RBC (iRBC) Ag, 28 and 90 days after challenge. However, infected RBC-specific central memory responses, as measured by IFN-c cultured ELISPOT, were low and unstable over time, despite CD4 1 T cells being highly proliferative by CFSE dilution, and showed an inverse relationship to parasite density. In support of the observation of poor memory, co-culture experiments showed reduced responses to common recall Ag, indicating malaria-specific regulatory activity. This activity could not be accounted for by the expression of IL-10, TGF-b, FOXP3 or CTLA-4, but proliferating T cells expressed high levels of CD95, indicating a pro-apoptotic phenotype. Lastly, there was an inverse relationship between FOXP3 expression, when measured 10 days after challenge, and ex vivo IFN-c measured more than 100 days later. This study shows that malaria infection elicits specific Th1 and Th2 effector cells, but concomitant weak central memory and regulatory activity, which may help to explain the short-lived immunity observed.

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Section: Introductionmentioning

confidence: 99%

Multiple functions of human T cells generated by experimental malaria challenge

et al. 2009

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“…In a harsh contrast, our results indicate that PL-MSCs stimulate strongly the expression of all maturation-related markers by DCs, their allostimulatory potential, and an IL-12-independent induction of Th1 polarization. Consequent increase of IFN-γ most probably caused down-regulation of IL-4 and IL-10 in those cocultures, via GATA-3-dependent mechanisms [36]. Several papers described the IL-12-independent induction of Th1 cells via IL-27-dependent activation of STAT-1 and T-bet [37].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells from periapical lesions modulate differentiation and functional properties of monocyte‐derived dendritic cells

et al. 2013

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Immunoregulatory mechanisms within periapical lesions (PLs) are as of yet unexplored. Considering the crucial role of DCs in controlling the immune response within PLs, the immunomodulatory properties of mesenchymal stem cells (MSCs), and the colocalization of MSCs and DCs in situ, we wondered whether MSCs from PLs modulate the development and functions of DCs. Using a model of monocyte-derived DCs, we showed that PL-MSCs inhibited differentiation of DCs via soluble factors, of which IL-6 had a minor effect, but did not impair their subsequent maturation induced by pro-inflammatory cytokines. However, upon maturation such DCs favored the production of Th2/Th17 cytokines by allogenic CD4 + lymphocytes in coculture, compared with mature DCs differentiated without PL-MSCs. PL-MSC-differentiated DCs, cultivated with pro-inflammatory cytokines and PL-MSCs, although phenotypically mature, exhibited poor allostimulatory activity, induced anergy, Th2 polarization, differentiation of suppressive CD4 + CD25 high CD39 + Treg-cell subsets via IDO-1-, ILT-3-, and ILT-4-dependent mechanisms, and increased production of TGF-β in the coculture. In contrast, DCs cultivated with PL-MSCs only during maturation stimulated proliferation and Th1 polarization of CD4 + T cells in an IL-12-independent manner. In conclusion, PL-MSCs significantly modulate the development and functions of DCs, depending on the phase of DCs development during which the interaction occurs. Keywords: Dendritic cells r Mesenchymal stem cells r Periapical lesions r Th polarizationAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPeriapical lesions (PLs) are a common pathology within the human population initiated by the bacterial invasion of the root canal and develop from an acute inflammatory response to the formation of granulomas or cysts infiltrated by various inflammatory cells [1].Correspondence: Prof. MiodragČolić e-mail: fakultet.vma@mod.gov.rs Furthermore, cytokines produced by Th cells have been shown to play a crucial role in PLs pathogenesis. Namely, Th1-and Th17-derived cytokines promote inflammation, bone resorption, and disease progression. Th2 cells seem to be important for the later phases of PLs development, whereas IL-10 and TGF-β produced by Treg cells seem to be important for the healing processes within PLs [2,3]. However, it is not yet clear which mediators and cells are involved crucially in the regulation of Th-cell commitment during the development, maintenance, and resolution of the disease.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 1862-1872 Immunomodulation 1863DCs are the key regulatory and decision-making cells with a unique ability to activate naive T cells and polarize their development. These cells can be differentiated in vitro from monocytes or CD34 + -progenitors with GM-CSF and IL-4, generating CD1a + CD14 − immature DCs (iDCs) [4]. Alternatively, in the absence of IL-4, GM-CSF induces the differ...

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“…DC maturation typically occurs upon recognition of danger signals via pattern recognition receptors, the most well defined of which being Toll-like receptors (TLRs). However, hostderived factors are also capable of inducing DC maturation, such as the cytokines IFN-c and TNF-a [29].…”

Section: Maturation Of Dcs: Provision Of Fully Functional Apcsmentioning

confidence: 99%

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

Tyler

Doherty

Moser

et al. 2015

Cellular Immunology

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a b s t r a c tUnconventional T cells are gaining center stage as important effector and regulatory cells that orchestrate innate and adaptive immune responses. Human Vc9/Vd2 T cells are amongst the best understood unconventional T cells, as they are easily accessible in peripheral blood, can readily be expanded and manipulated in vitro, respond to microbial infections in vivo and can be exploited for novel tumor immunotherapies. We here review findings that suggest that Vc9/Vd2 T cells, and possibly other unconventional human T cells, play an important role in bridging innate and adaptive immunity by promoting the activation and differentiation of various types of antigen-presenting cells (APCs) and even turning into APCs themselves, and thereby pave the way for antigen-specific effector responses and long-term immunological memory. Although the direct physiological relevance for most of these mechanisms still needs to be demonstrated in vivo, these findings may have implications for novel therapies, diagnostic tests and vaccines.Ó 2015 Published by Elsevier Inc. Introduction cd T cells represent a third lineage of lymphocytes expressingre-arranged antigen receptors that co-evolved with 'classical' B cells and ab T cells over 400 million years, arguing for a crucial and non-redundant contribution of each lymphocyte to effective immune responses, and hence the evolutionary survival of all jawed vertebrate species [1]. 30 years have passed since the accidental and unexpected cloning of the cd T cell receptor (TCR) and the subsequent realization that ab T cells and cd T cells are fundamentally different with respect to the types of antigens they recognize and the distinct effector functions triggered upon such recognition. However, the manifold contributions of cd T cells to homeostasis, inflammation, infection and tumor surveillance have historically been neglected and are only beginning to be integrated into comprehensive models of the immune system [1][2][3][4][5][6][7].1. Innate-like pattern recognition by human Vc9/Vd2 T cells Like other 'unconventional' T cells carrying an ab TCR such as mucosal-associated invariant T (MAIT) cells and natural killer T (NKT) cells, cd T cells are characterized by a markedly restrictedTCR usage that allows them to recognize self and non-self molecules in the absence of classical antigen presentation via MHC I or MHC II. Vc9/Vd2 + cd T cells represent the major cd T cell subset in human peripheral blood where they typically comprise 1-5% in healthy adults [8]. In many microbial infections, Vc9/Vd2 T cells increase locally and/or systemically [9,10] and can reach in excess of 50% of all peripheral T cells within a matter of days [11], revealing a fundamental role of this unconventional T cell population in acute disease and suggesting their exploitation for diagnostic and therapeutic purposes [12][13][14]. Vc9/Vd2 T cells uniformly respond to a class of low molecular weight molecules often referred to as 'phosphoantigens' that represent metabolites of the isoprenoid biosynthesis...

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Immunological decision‐making: how does the immune system decide to mount a helper T‐cell response?

Cited by 569 publications

References 103 publications

Multiple functions of human T cells generated by experimental malaria challenge

Multiple functions of human T cells generated by experimental malaria challenge

Mesenchymal stem cells from periapical lesions modulate differentiation and functional properties of monocyte‐derived dendritic cells

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

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