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T-cell intracellular antigen 1 (TIA1)-related/like (TIAR/TIAL1) protein is a multifunctional RNA-binding protein (RBP) involved in regulating many aspects of gene expression, independently or in combination with its paralog TIA1. TIAR was first described in 1992 by Paul Anderson's lab in relation to the development of a cell death phenotype in immune system cells, as it possesses nucleolytic activity against cytotoxic lymphocyte target cells. Similar to TIA1, it is characterized by a subcellular nucleo-cytoplasmic localization and ubiquitous expression in the cells of different tissues of higher organisms. In this paper, we review the relevant structural and functional information available about TIAR from a triple perspective (molecular, cellular and pathophysiological), paying special attention to its expression and regulation in cellular events and processes linked to human pathophysiology. [ABSTRACT FROM AUTHOR]

A model of B cell affinity selection is proposed, and an explanation of peripheral tolerance mechanisms through antibody repertoire editing is presented. We show that affinity discrimination between B cells is driven by a competition between obtaining T cell help and removal of B cells from the light zone, either through apoptosis or by a return to the dark zone of germinal centers. We demonstrate that this mechanism also allows for the negative selection of self reactive B cells and maintenance of B cell tolerance during the Germinal Center reaction. Finally, we demonstrate that clonal expansion upon return to the Germinal Center dark zone amplifies differences in the antigen affinity of B cells that survive the light zone. [ABSTRACT FROM AUTHOR]

The concept of oncolytic virus (OV)-mediated cancer therapy has been shifted from an operational virotherapy paradigm to an immunotherapy. OVs often induce immunogenic cell death (ICD) of cancer cells, and they may interact directly with immune cells as well to prime antitumor immunity. We and others have developed a number of strategies to further stimulate antitumor immunity and to productively modulate the tumor microenvironment (TME) for potent and sustained antitumor immune cell activity. First, OVs have been engineered or combined with other ICD inducers to promote more effective T cell cross-priming, and in many cases, the breaking of functional immune tolerance. Second, OVs may be armed to express Th1-stimulatory cytokines/chemokines or costimulators to recruit and sustain the potent antitumor immunity into the TME to focus their therapeutic activity within the sites of disease. Third, combinations of OV with immunomodulatory drugs or antibodies that recondition the TME have proven to be highly promising in early studies. Fourth, combinations of OVs with other immunotherapeutic regimens (such as prime-boost cancer vaccines, CAR T cells; armed with bispecific T-cell engagers) have also yielded promising preliminary findings. Finally, OVs have been combined with immune checkpoint blockade, with robust antitumor efficacy being observed in pilot evaluations. Despite some expected hurdles for the rapid translation of OV-based stateof- the-art protocols, we believe that a cohort of these novel approaches will join the repertoire of standard cancer treatment options in the near future. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are central to the adoptive immune response, and their function is regulated by diverse signals in a context-specific manner. Different DCs have been described in physiologic conditions, inflammation, and cancer, prompting a series of questions on how adoptive immune responses, or tolerance, develop against tumors. Increasing evidence suggests that tumor treatments induce a dramatic change on tumor-infiltrating lymphocytes and, in particular, on some DC subtypes. In this review, we summarize the latest evidence on the role of DCs in cancer and preliminary evidence on chemotherapy-associated antigens identified in human cancers. [ABSTRACT FROM AUTHOR]

Beyond their critical role in humoral immunity, B lymphocytes can employ a variety of immunomodulatory mechanisms including expression of the apoptosis-inducing molecule Fas ligand (FasL; CD178). Here, we extensively characterized the surface phenotype of FasL+ killer B cells, showing they are enriched in the IgMhighCD5+CD1dhigh B cell subset previously reported to contain a higher frequency of B cells producing interleukin-10 (IL-10). A rare population of B cells expressing IL-10 was present among FasL+ B cells, but most FasL+ B cells did not produce IL-10. We also identify interleukin-5 (IL-5) as a novel inducer of killer B cell function. Constitutively FasL+ B cells expressed higher levels of the IL-5 receptor, and treating B cells with IL-5 and CD40L resulted in the expansion of a B cell population enriched for FasL+ cells. B cells stimulated with IL-5 and CD40L were potent inducers of apoptosis in activated primary CD4+ T cells, and this killing function was antigen-specific and dependent upon FasL. IL-5 also enhanced IL-10 secretion in B cells stimulated with CD40L. Taken together these findings elucidate the relationship of FasL+ B cells and IL-10-producing B cells and demonstrate that IL-5 can induce or enhance both killer B cell activity and IL-10 secretion in B cells. Finally, we found that the killer B cell activity induced by IL-5 was completely blocked by IL-4, suggesting the existence of a previously unknown antagonistic relationship between these type-2 cytokines in modulating the activity of killer B cells. Targeting this IL-5/IL-4 signaling axis may therefore represent a novel area of drug discovery in inflammatory disorders. [ABSTRACT FROM AUTHOR]

Oral tolerance to auto antigens reduces the development of atherosclerosis in mouse models. However, the effect of immune tolerance to multiple self antigenic peptides in plaque progression and stabilization is not known. We studied the protective effect of mucosal tolerance to peptides from apolipoprotein B (ApoB; 661–680) and heat shock protein 60 (HSP60; 153–163), in combination with diet, in the prevention of atherosclerotic lesion progression and plaque stabilization in ApoBtm25gyLDLrtm1Her mice. We found that oral administration of five doses of a combination of ApoB and HSP60 peptides (20 µg/mice/dose) induced tolerance to both the peptides and reduced early plaque development by 39.9% better than the individual peptides (ApoB = 28.7%;HSP60 = 26.8%)(P<0.001). Oral tolerance to combination of peptides along with diet modification arrested plaque progression by 37.6% which was associated with increases in T-regulatory cell and transforming growth factor-β expression in the plaque and peripheral circulation. Reduced macrophage infiltration and tumor necrosis factor-α expression in the plaque was also observed. Tolerance with continued hypercholesterolemia resulted in 60.8% reduction in necrotic core area suggesting plaque stabilization, which was supported by reduction in apoptosis and increased efferocytosis demonstrated by greater expression of receptor tyrosine kinase Mer (MerTK) in the plaque. Tolerance to the two peptides also reduced the expression of matrix metalloproteinase 9, tissue factor, calprotectin, and increased its collagen content. Our study suggests that oral tolerance to ApoB and HSP60 peptide combination induces CD4+ CTLA4+ Tregs and CD4+CD25+Foxp3+ Tregs secreting TGF-β, which inhibit pathogenic T cell response to both peptides thus reducing the development and progression of atherosclerosis and provides evidence for plaque stabilization in ApoBtm25gyLDLrtm1Her mice. [ABSTRACT FROM AUTHOR]

Photochemotherapy is used both for solid tumors and in extracorporeal treatment of various hematologic disorders. Nevertheless, its development in oncology remains limited, because of the low selectivity of photosensitizers (PS) towards human tumor cells. To enhance PS efficiency, we recently covalently linked a porphyrin (TrMPyP) to a plant lectin (Morniga G), known to recognize with high affinity tumor-associated T and Tn antigens. The conjugation allowed a quick uptake of PS by Tn-positive Jurkat leukemia cells and efficient PS-induced phototoxicity. The present study was performed: (i) to evaluate the targeting potential of the conjugate towards tumor and normal cells and its phototoxicity on various leukemia cells, (ii) to investigate the mechanism of conjugate-mediated cell death. The conjugate: (i) strongly increased (×1000) the PS phototoxicity towards leukemic Jurkat T cells through an O-glycan-dependent process; (ii) specifically purged tumor cells from a 1:1 mixture of Jurkat leukemia (Tn-positive) and healthy (Tn-negative) lymphocytes, preserving the activation potential of healthy lymphocytes; (iii) was effective against various leukemic cell lines with distinct phenotypes, as well as fresh human primary acute and chronic lymphoid leukemia cells; (iv) induced mostly a caspase-independent cell death, which might be an advantage as tumor cells often resist caspase-dependent cell death. Altogether, the present observations suggest that conjugation with plant lectins can allow targeting of photosensitizers towards aberrant glycosylation of tumor cells, e.g. to purge leukemia cells from blood and to preserve the normal leukocytes in extracorporeal photochemotherapy. [ABSTRACT FROM AUTHOR]

T lymphocytes expressing a chimeric antigen receptor (CAR) targeting the CD19 antigen (CAR.19) may be of value for the therapy of B-cell malignancies. Because the in vivo survival, expansion and anti-lymphoma activity of CAR.19(+) T cells remain suboptimal even when the CAR contains a CD28 costimulatory endodomain, we generated a novel construct that also incorporates the interleukin-15 (IL-15) gene and an inducible caspase-9-based suicide gene (iC9/CAR.19/IL-15). We found that compared with CAR.19(+) T cells, iC9/CAR.19/IL-15(+) T cells had: (1) greater numeric expansion upon antigen stimulation (10-fold greater expansion in vitro, and 3- to 15-fold greater expansion in vivo) and reduced cell death rate (Annexin-V(+)/7-AAD(+) cells 10+/-6% for iC9/CAR.19/IL-15(+) T cells and 32+/-19% for CAR.19(+) T cells); (2) reduced expression of the programmed death 1 (PD-1) receptor upon antigen stimulation (PD-1(+) cells <15% for iC9/CAR.19/IL-15(+) T cells versus >40% for CAR.19(+) T cells); and (3) improved antitumor effects in vivo (from 4.7- to 5.4-fold reduced tumor growth). In addition, iC9/CAR.19/IL-15(+) T cells were efficiently eliminated upon pharmacologic activation of the suicide gene. In summary, this strategy safely increases the anti-lymphoma/leukemia effects of CAR.19-redirected T lymphocytes and may be a useful approach for treatment of patients with B-cell malignancies. [ABSTRACT FROM AUTHOR]

Memory B and plasma cells (PCs) are generated in the germinal center (GC). Because follicular helper T cells (TFH cells) have high expression of the immunoinhibitory receptor PD-1, we investigated the role of PD-1 signaling in the humoral response. We found that the PD-1 ligands PD-L1 and PD-L2 were upregulated on GC B cells. Mice deficient in PD-L2 (Pdcd1lg2−/−), PD-L1 and PD-L2 (Cd274−/−Pdcd1lg2−/−) or PD-1 (Pdcd1−/−) had fewer long-lived PCs. The mechanism involved more GC cell death and less TFH cell cytokine production in the absence of PD-1; the effect was selective, as remaining PCs had greater affinity for antigen. PD-1 expression on T cells and PD-L2 expression on B cells controlled TFH cell and PC numbers. Thus, PD-1 regulates selection and survival in the GC, affecting the quantity and quality of long-lived PCs. [ABSTRACT FROM AUTHOR]

The relative importance of the intrinsic and extrinsic apoptotic pathways in the control of haematopoietic cell homeostasis has been a matter of debate for many years. Cell death is omnipresent in this cellular compartment and ensures the removal of cells that are not properly equipped to assume their function as well as those that have assumed function but are no longer required. In this Review we focus on the roles of CD95 (also known as FAS) and BCL-2-interacting mediator of cell death (BIM), two major regulators of apoptosis in T cell homeostasis, with a particular emphasis on their cooperation in the shutdown of T cell responses. [ABSTRACT FROM AUTHOR]

Experimental visceral leishmaniasis (VL) represents an exquisite model to study CD8+ T cell responses in a context of chronic inflammation and antigen persistence, since it is characterized by chronic infection in the spleen and CD8+ T cells are required for the development of protective immunity. However, antigen-specific CD8+ T cell responses in VL have so far not been studied, due to the absence of any defined Leishmania-specific CD8+ T cell epitopes. In this study, transgenic Leishmania donovani parasites expressing ovalbumin were used to characterize the development, function, and fate of Leishmania-specific CD8+ T cell responses. Here we show that L. donovani parasites evade CD8+ T cell responses by limiting their expansion and inducing functional exhaustion and cell death. Dysfunctional CD8+ T cells could be partially rescued by in vivo B7-H1 blockade, which increased CD8+ T cell survival but failed to restore cytokine production. Nevertheless, B7-H1 blockade significantly reduced the splenic parasite burden. These findings could be exploited for the design of new strategies for immunotherapeutic interventions against VL. [ABSTRACT FROM AUTHOR]

Caspase-8, a cysteine-protease, initiates apoptosis when activated by death receptors. Caspase-8 is also essential for initiating T lymphocyte proliferation following T-cell antigen receptor (TCR) signaling. Given these disparate functions of caspase-8, we sought to determine whether this represented only a difference in the magnitude of caspase-8 activation, or different intracellular locations of active caspase-8. We demonstrate by high-resolution multicolor confocal laser scanning microscopy an aggregation of active caspase-8 within membrane lipid rafts in T cells stimulated with anti-CD3. This suggests that following TCR stimulation active caspase-8 physically interacts with lipid raft proteins, possibly to form a signaling platform. In contrast, Fas stimulation of T cells resulted in a much more profound activation of caspase-8 that was exclusively cytosolic. These confocal microscopic findings were confirmed using discontinuous sucrose gradient ultracentrifugation to isolate lipid raft versus cytosolic components. This sequestration model of caspase-8 activation was further supported by the observation that a classic caspase-8 substrate, BID, was not cleaved in CD3-stimulated T cells, but was cleaved after Fas engagement. Our data support a model that the location of active caspase-8 may profoundly influence its functional capacity as a regulator of either cell cycling or cell death.Cell Death and Differentiation (2008) 15, 1701–1711; doi:10.1038/cdd.2008.100; published online 11 July 2008 [ABSTRACT FROM AUTHOR]

Background: Regulatory T cell (Treg) based immunotherapy is a potential treatment for several immune disorders. By now, this approach proved successful in preclinical animal transplantation and auto-immunity models. In these models the success of Treg based immunotherapy crucially depends on the antigen-specificity of the infused Treg population. For the human setting, information is lacking on how to generate Treg with direct antigen-specificity ex vivo to be used for immunotherapy. Methodology/Principal Findings: Here, we demonstrate that in as little as two stimulation cycles with HLA mismatched allogeneic stimulator cells and T cell growth factors a very high degree of alloantigen-specificity was reached in magnetic bead isolated human CD4posCD25high Treg. Efficient increases in cell numbers were obtained. Primary allogeneic stimulation appeared a prerequisite in the generation of alloantigen-specific Treg, while secondary allogeneic or polyclonal stimulation with anti-CD3 plus anti-CD28 monoclonal antibodies enriched alloantigen-specificity and cell yield to a similar extent. Conclusions/Significance: The ex vivo expansion protocol that we describe will very likely increase the success of clinical Treg-based immunotherapy, and will help to induce tolerance to selected antigens, while minimizing general immune suppression. This approach is of particular interest for recipients of HLA mismatched transplants. [ABSTRACT FROM AUTHOR]

Acute HIV-1 infection of CD4 T cells often results in apoptotic death of infected cells, yet it is unclear what evolutionary advantage this offers to HIV-1. Given the independent observations that acute T cell HIV-1 infection results in (1) NF-κB activation, (2) caspase 8 dependent apoptosis, and that (3) caspase 8 directly activates NF-κB, we questioned whether these three events might be interrelated. We first show that HIV-1 infected T cell apoptosis, NF-κB activation, and caspase 8 cleavage by HIV-1 protease are coincident. Next we show that HIV-1 protease not only cleaves procaspase 8, producing Casp8p41, but also independently stimulates NF-κB activity. Finally, we demonstrate that the HIV protease cleavage of caspase 8 is necessary for optimal NF-κB activation and that the HIV-1 protease specific cleavage fragment Casp8p41 is sufficient to stimulate HIV-1 replication through NF-κB dependent HIV-LTR activation both in vitro as well as in cells from HIV infected donors. Consequently, the molecular events which promote death of HIV-1 infected T cells function dually to promote HIV-1 replication, thereby favoring the propagation and survival of HIV-1. [ABSTRACT FROM AUTHOR]

Classically, HLA-DR expressed on antigen presenting cells (APC) initiates lymphocyte activation via presentation of peptides to TCR bearing CD4+ T-Cells. Here we demonstrate that HLA-DR alpha 2 domain (sHLA-DRα2) also induces negative signals by engaging TIRC7 on lymphocytes. This interaction inhibits proliferation and induces apoptosis in CD4+ and CD8+ T-cells via activation of the intrinsic pathway. Proliferation inhibition is associated with SHP-1 recruitment by TIRC7, decreased phosphorylation of STAT4, TCR-ζ chain & ZAP70, and inhibition of IFN-γ and FasL expression. HLA-DRα2 and TIRC7 co-localize at the APC-T cell interaction site. Triggering HLA-DR - TIRC7 pathway demonstrates that sHLA-DRα2 treatment inhibits proinflammatory-inflammatory cytokine expression in APC & T cells after lipopolysaccaride (LPS) stimulation in vitro and induces apoptosis in vivo. These results suggest a novel antiproliferative role for HLA-DR mediated via TIRC7, revise the notion of an exclusive stimulatory interaction of HLA-DR with CD4+ T cells and highlights a novel physiologically relevant regulatory pathway. [ABSTRACT FROM AUTHOR]

Many studies have shown the central importance of the co-receptors CD28, inducible costimulatory molecule (ICOS) and cytotoxic T lymphocyte antigen 4 (CTLA4) in the regulation of many aspects of T-cell function. CD28 and ICOS have both overlapping and distinct functions in the positive regulation of T-cell responses, whereas CTLA4 negatively regulates the response. The signalling pathways that underlie the function of each of the co-receptors indicate their shared and unique properties and provide compelling hints of functions that are as yet uncovered. Here, we outline the shared and distinct signalling events that are associated with each of the co-receptors and provide unifying concepts that are related to signalling functions of these co-receptors. [ABSTRACT FROM AUTHOR]

Background: Activation-induced apoptosis is believed to limit cell proliferation and eliminate the high number of activated cells during an immune response. Methods: Activation-induced apoptosis was investigated in splenic T cells isolated from young (6 months) and old (24 months) male Fischer 344 rats. The cells were incubated with anti-CD3, concanavalin A or staphylococcal enterotoxin B (primary stimulus) for 72 h, followed by restimulation with anti-CD3 or concanavalin A (secondary stimulus). Apoptosis was assessed by DNA fragmentation assay and DNA gel electrophoresis. The expression of the apoptotic marker CD95 was analyzed by flow cytometry and the relative levels of CD95 ligand, Bcl-2 and Bax protein were measured by immunoblotting. Results: It was shown that DNA fragmentation was very low in the unstimulated T cells from both young and old rats. However, the level of DNA fragmentation was 45–55% greater in the activated T cells from old rats than in the activated T cells from young rats. The increase in DNA fragmentation was paralleled by an increase in the proportion of cells expressing the CD95 molecule. The proportion of CD95+ cells was approximately 40% higher in T cells from old rats than in T cells from young rats. In addition, it was found that the expression of CD95 ligand and Bax increased and Bcl-2 decreased in the activated T cells from old rats compared to the activated T cells from young rats. Conclusion: Our data suggest that the increase in sensitivity of T cells to apoptosis with age may contribute to age-associated immune dysfunction and disorders.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

FIV is a lentivirus infection of cats which induces an immunodeficiency syndrome associated with early qualitative defects in antigen-specific T cell function and with late quantitative defects in CD4+ T lymphocytes. We have observed that peripheral blood mononuclear cells (PBMC) from FIV-infected cats have impaired survival in culture. The mechanism of this in vitro dysfunction and depletion is not known. We have proposed that inappropriate induction of programmed cell death (apoptosis) could account for these In vitro defects. Here, we report that PBMC from FIV-infected cats, with impaired T cell blastogenesis and impaired survival in vitro, undergo an active cell death upon culture, which has the morphological and biochemical characteristics of programmed cell death (PCD), Apoptosis occurred in all six asymptomatic FIV-infected cats, and in none of the nine uninfected cats, which were studied. Changes in cell morphology under both light and electron microscopy, and fragmentation of genomic DNA were characteristic for apoptosing cells. Ceil death was spontaneous and occurred in the absence of any stimuli, and culture with the T cell mitogen, concanavalin A (Con A), did not significantly enhance cell death. Activation-induced cell death was inhibited, in a dose-dependent manner, by addition to the incubation medium of zinc, which has been shown to inhibit the action of endonuclease responsible for the characteristic fragmentation of DNA. Since apoptosis has recently been implicated in AIDS pathoiiencsis, FIV infection may prove useful to study this aspect of retroviral, in particular HIV, infection. [ABSTRACT FROM AUTHOR]