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Summary: The immune system plays a critical role in protecting the host against infection but is subject to numerous levels of control that are necessary to prevent pathological, tissue-damaging responses. Inappropriate inflammatory immune responses to self-antigens, innocuous commensal microorganisms, or environmental antigens can lead to chronic, debilitating, and degenerative diseases. Regulatory T cells have an essential, non-redundant, and dominant function in preventing pathological immune responses, as shown by the development of systemic fatal autoimmunity in humans and animals with a genetic deficiency in regulatory T cells. In addition to controlling immune responses, there is a growing understanding that regulatory T cells also contribute directly to tissue homeostasis by promoting tissue regeneration and repair. For these reasons, the prospect of enhancing regulatory T-cell numbers and/or function in patients represents an appealing therapeutic opportunity with potential applications in many diseases, including some where the pathological role of the immune system has only recently been recognized. Approaches to enhance regulatory T cells are now starting to be explored in clinical studies in humans. This review series brings together papers highlighting the Treg-enhancing approaches that are most advanced clinically and examples of therapeutic opportunities based on our growing understanding of regulatory T-cell functions. [ABSTRACT FROM AUTHOR]

Leukocyte adhesion is important for the proper functioning of the immune system. While leukocyte homing is mediated by adhesion receptors, the activation of these receptors is modulated by intracellular signaling molecules. In Leukocyte Adhesion Deficiency Type 3, the loss of the kindlin-3 prevents the activation of Leukocyte Function-associated Antigen-1 (LFA-1), which leads to a defect in adhesion, causing recurrent infections and bleeding disorders. Here, we use Integrated Signaling Adhesive Dynamics, a computer model of leukocyte rolling and adhesion combined with a simulated intracellular signaling cascade, to predict the response of T cells to depletion of kindlin-3. Our model predicts that cell adhesion is hypersensitive to the amount of kindlin-3 in the cell, while the rolling velocity is independent of kindlin-3 concentration. In addition, our simulation predicted that the time to stop, an important metric of adhesion, would increase with decreasing kindlin-3 expression. These predictions were confirmed experimentally in experiments using Jurkat cells with reduced expression of kindlin-3. These results suggest that Adhesive Dynamics is a versatile tool for quantifying adhesion in the immune response and predicting the effects of engineering cellular components. [ABSTRACT FROM AUTHOR]

It has been shown that hematological traits can act as important indicators of immune function in both humans and livestock. T lymphocytes are key components of the adaptive immune system, playing a critical role in immune response. To identify genomic regions affecting hematological traits and T lymphocyte subpopulations, we performed both a SNP-based genomewide association study (GWAS) and a haplotype analysis for 20 hematological traits and 8 T cell subpopulations at 3 different time points (d 20, 33, and 35) in a Duroc × Erhualian F2 inter-cross population. Bonferroni correction was used to calculate the threshold P-values for suggestive and 5% genomewide significance levels. In total, for SNP-based GWAS, we detected 96 significant SNP, including 15 genomewide-significant SNP, associated with 23 hematological traits and 234 significant SNP, including 27 genomewide-significant SNP, associated with 8 T cell subpopulations. Meanwhile, we identified 563 significant SNP, including τ genomewide-significant SNP, associated with 5 hematological traits and 2,407 significant SNP, including 1,261 genomewide-significant SNP, associated with 8 T cell subpopulations by haplotype analysis. Among the significant regions detected, we propose both the NCK adaptor protein 2 (NCK2) gene and the four and a half LIM domains 2 (FHL2) gene on SSC3 as plausible candidate genes associated with CD8 + T lymphocytes at d 20. The findings provide insights into the basis of molecular mechanisms that are involved with immune response in the domestic pig and would aid further identification of causative mutations. [ABSTRACT FROM AUTHOR]8- T lymphocytes at d 20. The findings provide insights into the basis of molecular mechanisms that are involved with immune response in the domestic pig and would aid further identification of causative mutations. [ABSTRACT FROM AUTHOR]

This review discusses three inter-related topics: (1) the immaturity of the neonatal and infant immune response; (2) heterologous immunity, where prior infection history with unrelated pathogens alters disease outcome resulting in either enhanced protective immunity or increased immunopathology to new infections, and (3) epidemiological human vaccine studies that demonstrate vaccines can have beneficial or detrimental effects on subsequent unrelated infections. The results from the epidemiological and heterologous immunity studies suggest that the immune system has tremendous plasticity and that each new infection or vaccine that an individual is exposed to during a lifetime will potentially alter the dynamics of their immune system. It also suggests that each new infection or vaccine that an infant receives is not only perturbing the immune system but is educating the immune system and laying down the foundation for all subsequent responses. This leads to the question, is there an optimum way to educate the immune system? Should this be taken into consideration in our vaccination protocols? [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases are characterized by a deregulated immune response targeting the gut bacterial flora. Mucosal-associated invariant T ( MAIT) cells are major histocompatibility complex ( MHC) class Ib-restricted innate-like lymphocytes with anti-bacterial functions. They display an effector/memory phenotype and are found in large numbers in the blood, mucosae and liver. They have also been implicated in inflammatory diseases such as multiple sclerosis. Therefore, we aimed to analyse the possible involvement of MAIT cells in Crohn's disease ( CD) and ulcerative colitis ( UC). To this end, a phenotypical and functional analysis of MAIT cells isolated from the blood of healthy subjects, CD and UC patients was undertaken. MAIT cells were also quantified in ileal biopsies of CD patients. The frequency of blood MAIT cells was specifically reduced in IBD patients compared with healthy donors, whereas it was dramatically greater in the inflamed versus healthy tissue. MAIT cells were activated as they expressed significantly more the Ki67 antigen, and this was accompanied by phenotypical changes such as increased expression of natural killer ( NK)G2 D and B and T lymphocyte attenuator ( BTLA). Finally, in-vitro-activated MAIT cells from CD and UC patients secreted significantly more interleukin ( IL)-17, together with a decreased interferon ( IFN)-γ in CD but an increased IL-22 in UC. These data show that MAIT cells are activated in IBD, which results in an increased recruitment towards the inflamed tissues, an altered phenotype and a switch in the pattern of cytokine secretion. This is the first demonstration that MAIT cells are immune players in IBD, whose precise functions in this context need to be addressed. [ABSTRACT FROM AUTHOR]

Cancer may occur as a result of abnormal host immune system tolerance. Recent studies have confirmed the occurrence of spontaneous and induced antitumor immune responses expressed as the presence of tumor-infiltrating T cells in the tumor microenvironment in some cancer models. This finding has been recognized as a good prognostic factor in several types of tumors. Some chemotherapy agents, such as anthracyclines and gemcitabine, are effective boosters of the immune response through tumor-specific antigen overexpression after apoptotic tumor cell destruction. Other strategies, such as GM-CSF or interleukin-2, are pursued to increase immune cell availability in the tumor vicinity, and thus improve both antigen presentation and T-cell activation and proliferation. In addition, cytotoxic T lymphocyte antigen 4 -- blocking monoclonal antibodies enhance immune activity by prolonging T-cell activation. Strategies to stimulate the dormant immune system against tumors are varied and warrant further investigation of their applications to cancer therapy in the future. [ABSTRACT FROM AUTHOR]

Knowledge of the role of origin-related, environmental, sex, and age factors on host defence mechanisms is important to understand variation in parasite intensity. Because alternative components of parasite defence may be differently sensitive to various factors, they may not necessarily covary. Many components should therefore be considered to tackle the evolution of host–parasite interactions. In a population of barn owls ( Tyto alba), we investigated the role of origin-related, environmental (i.e. year, season, nest of rearing, and body condition), sex, and age factors on 12 traits linked to immune responses [humoral immune responses towards sheep red blood cells (SRBC), human serum albumin (HSA) and toxoid toxin TT, T-cell mediated immune response towards the mitogen phytohemagglutinin (PHA)], susceptibility to ectoparasites (number and fecundity of Carnus haemapterus, number of Ixodes ricinus), and disease symptoms (size of the bursa of Fabricius and spleen, proportion of proteins that are immunoglobulins, haematocrit and blood concentration in leucocytes). Cross-fostering experiments allowed us to detect a heritable component of variation in only four out of nine immune and parasitic parameters (i.e. SRBC- and HSA-responses, haematocrit, and number of C. haemapterus). However, because nestlings were not always cross-fostered just after hatching, the finding that 44% of the immune and parasitic parameters were heritable is probably an overestimation. These experiments also showed that five out of these nine parameters were sensitive to the nest environment (i.e. SRBC- and PHA-responses, number of C. haemapterus, haematocrit and blood concentration in leucocytes). Female nestlings were more infested by the blood-sucking fly C. haemapterus than their male nestmates, and their blood was less concentrated in leucocytes. The effect of year, season, age (i.e. reflecting the degree of maturation of the immune system), brood size, position in the within-brood age hierarchy, and body mass strongly differed between the 12 parameters. Different components of host defence mechanisms are therefore not equally heritable and sensitive to environmental, sex, and age factors, potentially explaining why most of these components did not covary. © 2007 The Linnean Society of London, Biological Journal of the Linnean Society, 2007, 90, 703–718. [ABSTRACT FROM AUTHOR]

Transforming growth factor (TGF)-β has been demonstrated to play a key role in the regulation of the immune response, mainly by its suppressive function towards cells of the immune system. In humans, the effect of TGF-β on antigen-specific established memory T cells has not been investigated yet. In this study antigen-specific CD4+ T cell clones (TCC) were used to determine the effect of TGF-β on antigen-specific proliferation, the activation status of the T cells and their cytokine production. This study demonstrates that TGF-β is an adequate suppressor of antigen-specific T cell proliferation, by reducing the cell-cycle rate rather than induction of apoptosis. Addition of TGF-β resulted in increased CD69 expression and decreased CD25 expression on T cells, indicating that TGF-β is able to modulate the activation status of in vivo differentiated T cells. On the contrary, the antigen-specific cytokine production was not affected by TGF-β. Although TGF-β was suppressive towards the majority of the T cells, insensitivity of a few TCC towards TGF-β was also observed. This could not be correlated to differential expression of TGF-β signaling molecules such as Smad3, Smad7, SARA (Smad anchor for receptor activation) and Hgs (hepatocyte growth factor-regulated tyrosine kinase substrate). In summary, TGF-β has a pronounced inhibitory effect on antigen-specific T cell proliferation without modulating their cytokine production. [ABSTRACT FROM AUTHOR]