[31] To make things more complicated, not all inflammatory milieux produce the same outcome. Some studies have indicated an important role

for toll-like receptors (TLR), membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes and mediate the activation of immune responses of both innate and adaptive types. Mesenchymal stromal cells express a large number of TLR, the stimulation of which has been shown to profoundly affect MSC immunomodulatory properties as well as their migratory phenotype. It is well established that MSC express a number of TLR at both RNA and protein JNK inhibitor mw levels. High mRNA expression of TLR1, TLR2, TLR3, TLR4, TLR5 and TLR6 has been consistently detected, whereas TLR2, TLR3, TLR4, TLR7 and TLR9 expression has been reported by flow cytometry. Unfortunately, there is little consensus about the pattern of their expression in MSC with the major confounding factors being the heterogeneity of MSC preparations and the modality of TLR detection. The expression of TLR on MSC has also been functionally assessed. Although

TLR3 and TLR4 binding antagonises MSC immunosuppressive activity,[60] the stimulation of the same receptor on isolated MSC before their use in culture boosts MSC immunosuppressive activity.[61] It has been shown that TLR3 and TLR4 activation induces the production of pro-inflammatory mediators, such as IL-1, IL-6, IL-8 and CCL5 together with the expression of iNOS, and TNF-related Ibrutinib solubility dmso apoptosis-inducing ligand (TRAIL).[62] It should be noted however that the time of exposure to TLR ligands and the concomitant presence of other cytokines are likely to

add layers of complexity. Following low-level, short-term TLR-priming, Waterman[63] observed opposing effects of TLR3 or TLR4 stimulation. Last, targeting TLR2 results in the up-regulation of galectin-3, known to modulate T-cell proliferation.[64] The possibility of alternating the immunomodulatory properties of MSC depending on the inflammatory environment to which they are exposed has profound implications on how to harness PI3K inhibitor their therapeutic potentials. The studies conducted to investigate MSC therapeutics in graft-versus-host disease (GvHD) are fully consistent with the biological features so far identified. Irrespective of the animal models used, MSC are effective at treating GvHD only when administered at fairly specific intervals.[65-67] At these time-points, the levels of inflammatory cytokines like IFN-γ are particularly high and therefore more likely to promote MSC immunosuppressive activity. The clinical studies are fully in accord with these data.

32 TLR agonists are therefore potent stimulants of IFN-I release by antigen-presenting cells.33 To mimic the immune response observed selleck chemicals llc during viral infections, PBMC were treated overnight with poly(I:C) in order to induce endogenous production of IFN-I. In a preliminary study, we confirmed that poly(I:C) treatment of PBMC from several donors resulted in IFN-α secretion ranging between 30 and 200 pg/ml (data not shown). The addition of poly(I:C) 24 hr prior to anti-CD3 activation led to an average decrease of 40% (P = 0·007) in the production of aTregs (Fig. 4; for cell numbers see Fig. S2). However, in

contrast to IFN-α, poly(I:C) had an inconsistent effect on aTeffs (Figs 4 and S2), which may result from the effects of other cytokines (e.g. IFN-β) induced by TLR3 ligation. To further address the role of endogenously produced IFN-I in the suppression of

aTregs, these assays were also performed in the presence of an antibody that blocks binding of IFN-I to cellular receptors, as well as neutralizing antibodies against TNF-α and IL-6 (Figs 4 and S2). Blocking of IFNα/β receptor produced a significant (P = 0·0001) normalization of Treg activation, with an average recovery Selleck CP 868596 of 92% in Treg activation. In contrast, the presence of antibodies against TNF-α and IL-6 had a minimal effect on the suppression of Treg activation induced by poly(I:C). Taken together, these data suggest that innate signals that mimic the immune response to viral infections are able to suppress Treg activation, and that IFN-I probably plays a major role during this process. As IL-2 plays a critical role in Treg development and proliferation,34,35 and because it has previously been shown that IFN-α is a potent

inhibitor of IL-2 production,36 we addressed whether the reduced expansion of Tregs in the presence of IFN-α might result from a decrease in IL-2 production in the polyclonally stimulated PBMC cultures. To that end, IL-2 levels in the culture supernatants were measured by ELISA at 24 and 48 hr post anti-CD3 activation of PBMC in the absence or presence of exogenous IFN-α (1000 U/ml) Tau-protein kinase (Fig. 5). IFN-α reduced the production of IL-2 in polyclonally activated PBMC by an average of 45% in the first 24 hr (P = 0·01) and by an average of 55% after 48 hr (P = 0·05) (Fig. 5a). This reduction in IL-2 production correlated with a 66% (P = 0·04) reduction in the generation of aTregs (Fig. 5b). In order to address whether IL-2 inhibition by IFN-α could be reversed in activated PBMC, we tested whether suppression of Treg activation was reversed by exogenous IL-2 (100 Units/ml). Indeed, Treg activation in the presence of IFN-α was improved almost threefold (P = 0·01) by the addition of IL-2 (Fig. 5b), strongly suggesting that down-regulation of endogenous IL-2 production may play a critical role in IFN-α-mediated suppression of Treg activation.

These included a T cell subpopulation shift and an evidence for polyclonal B cell activation and high levels of circulating immune complexes [12]. Recently, Farkas et al. assessed the clinical data and immunoserological parameters of 130 Hungarian HAE patients. In agreement with the

above early study, 12% were found to suffer from immunoregulatory disorders and in addition the authors revealed the presence of autoantibodies in 47·7% of their HAE patients. Interestingly, increased production of autoantibodies, especially anti-nuclear antibodies, was also found in a control group of patients with non-C1 INH-deficient angioedema [13]. The aim of this study was to characterize the autoantibody profile in a large selleck products group of HAE patients. Furthermore, we analysed the phenotype, including Toll-like receptor (TLR)-9 expression and activation status of memory B cells isolated from patients with HAE, aiming to propose a possible mechanism for this B cell autoreactivity. We studied 61 patients with C1-INH deficiency

36 women and 25 men aged 43·3 ± 14 [mean ± standard deviation (s.d.) years, range 19–70 years]. Fifty-six had type 1 HAE and five had type 2 HAE. The diagnosis of HAE was based on the patient’s family history, clinical DNA Damage inhibitor presentation and laboratory results of levels of functional or antigenic C1 esterase inhibitor of less than half the normal levels. The patients were recruited from Israel (30 patients, 15 women, 15 men) and Italy (31 patients, click here 21 women, 10 men). Thirty-seven of 61 (60%) patients were treated with

danazol. Seventy healthy age- and sex-matched volunteers from the medical staff of our medical centre served as controls. Twenty controls were used for the B cell phenotype and activation profiles and 50 controls were used for the analysis of serum autoantibodies. The controls were healthy by self-report, with no clinical symptoms of autoimmune or infectious diseases. The local Committee on Human Experimentation approved the study. Blood samples were drawn from HAE patients during their visits in the out-patient clinic and the serum was stored at –20°C until assayed. The detection of anti-nuclear antibodies (ANA) in the patients’ serum was assayed by indirect immunofluorescence using slides covered with HEp-2 cells (Zeus Scientific, Inc., Branchburg, NJ, USA). Anti- extractable nuclear antigen (ENA) antibodies were analysed using a commercial enzyme-linked immunosorbent assay (ELISA) kit (Orgentec Diagnostika GmbH, Mainz, Germany). Rheumatoid factor was assayed by the 2-min latex slide test (Biokit, SA, Barcelona, Spain). Anti-cardiolipin antibodies were analysed using a commercial ELISA kit (Genesis Diagnostics, Cambridgeshire, UK). Antibodies to tissue transglutaminase (ttG) were analysed using a commercial ELISA kit (Inova Diagnostics, Inc., San Diego, CA, USA) Anti-endomysial antibodies were analysed using a commercial ELISA kit (Inova Diagnostics, Inc.

Ogg1 mRNA levels were significantly higher in Nlrp3−/− DCs compared with WT DCs (Fig. 1B and 4E). These data suggested that the NLRP3 activators prompt DNA damage and, at later time points,

the inflammasome may affect the DNA damage repair machinery. To identify PXD101 possible mechanisms that might account for the differential biological response to DNA damage observed in WT DCs compared with Nlrp3−/− DCs, we examined the activation of signaling cascades induced by DNA damage. We first used western blot to detect activating phosphorylation of ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) following DNA breaks induced by MSU treatment or γ-radiation. Phosphorylation of ATR (S428) after MSU treatment (Fig. 5A) or γ-radiation at both low and high doses (Fig. 5B) was enhanced in WT DCs compared to Nlrp3−/− DCs. ATM (S1981) was increased in WT DCs upon γ-radiation and substantially reduced in Nlrp3−/− or casp-1−/− DCs (Fig. 5B). NBS1, a protein involved in DNA repair and genotoxic stress responses, was found to be highly phosphorylated in Nlrp3−/− DCs compared with WT DCs (Fig. 5A). These data are in accordance with the increase SB203580 ic50 in DNA breaks observed in WT DCs compared with Nlrp3−/− and casp-1−/− DCs (Fig. 2 and 3A and D) and indicate that

DNA repair was more effective in cells that lacked Nlrp3 expression. The transcription factor p53 is a major effector of the DDR through its activation of the transcription of target genes involved in cell cycle arrest, DNA repair, and cell death [13]. We therefore assessed the activity of the p53 pathway in response to cellular stress in WT, Nlrp3−/−, or casp-1−/− DCs. p53 phosphorylation at Ser15 and Ser20 was induced early in WT, Nlrp3−/−, and casp-1−/− DCs after MSU treatment or exposure to γ-radiation Morin Hydrate (Fig. 6A–C). However, WT cells exhibited markedly prolonged p53 activation, while total p53 levels were similar for Nlrp3−/−, casp-1−/−,

and WT DCs (Fig. 6A–C). These results indicate that p53 is more stable in WT DCs than in DCs that lack the NLRP3 inflammasome and suggest that the p53 pathway is involved in NLRP3-mediated cell death. Accordingly, we found that p21 protein, which protects cells from p53-induced apoptosis by promoting cell cycle arrest and repair, was upregulated in Nlrp3−/− DCs, whereas p21 protein levels were not increased in WT DCs following treatments (Fig. 6A and B). Moreover, we also monitored the levels of DNA damage and p53 phosphorylation in vivo in a mouse model of MSU-mediated peritonitis. A substantial increase in γH2AX and p53 phosphorylation was seen 6 h after MSU injection but not in control mice, indicating that the p53 pathway is also activated in vivo (Fig. 6D). We finally determined whether pyroptosis, a casp-1-dependent cell death, was triggered to different extents in WT and Nlrp3−/− DCs following MSU treatment.

brasiliensis-sensitized mice exhibited efficient fungicidal activity in vitro [14]. In addition, neutrophil fungicidal activity is higher in resistant mice than in susceptible mice [15]. Pina et al. [16], in a complete study of neutrophil depletion during murine infection, have shown that these cells are essential for host defence to Pb infection and that host genetic pattern exerts an important influence on neutrophil functions. Together,

the findings reported to date clearly demonstrate that neutrophils may play an important effector and immunomodulatory role, especially in the early stages of infection, contributing to Pb host resistance. Nonetheless, some studies show that neutrophil Staurosporine research buy functions, including fungus killing, require activation

with cytokines and other factors. In our laboratory, IFN-γ, TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-15 have been observed to activate human neutrophils for fungicidal activity by a mechanism dependent on H2O2 and superoxide anion [17, 18]. The specific detection of microorganisms by innate cells is mediated by pattern recognition receptors (PRR), germ line-encoded receptors that ACP-196 recognize microbial structures referred to as pathogen-associated molecular pattern [19]. Toll-like receptors (TLR) are essential PRR that mediate recognition of microbial structures, such as those of fungi, as well as the subsequent inflammatory and adaptative responses [20–23]. Because neutrophils and TLR are respectively the prototypical cell and not receptor of innate immune response, the role of individual TLR on neutrophil functions has been investigated [24–27], including that involved in the response of these

cells to fungi [28]. Various stimuli have been shown to regulate expression of TLR in neutrophils, including pathogen structures and TLR ligands, such as lipopolysaccharide (LPS), and pro-inflammatory cytokines, such as IL-1β, TNF-α, GM-CSF and IFN-γ [24, 26, 29–31]. In view of these observations, studies conducted to evaluate the role of TLR on neutrophil functions against Pb may contribute to a better understanding of parasite/host relationship in the mycosis. In the present study, we aimed at evaluating TLR2 and TLR4 expression on human neutrophils activated with GM-CSF, IL-15, TNF-α or IFN-γ and challenged with Pb18, a virulent strain of the fungus. Moreover, we asked if these receptors have a role on fungicidal activity, H2O2 and IL-6, IL-8, TNF-α and IL-10 production by activated and challenged cells. Healthy individuals.  Twenty-eight healthy blood donors from University Hospital of the Botucatu Medical School, São Paulo State University, Brasil (age range 20–50 years) were included in the present work. The study was approved by Ethics Committee of Botucatu Medical School, and informed consent was obtained from all the blood donors. Fungi.  The high virulent strain of P.

This study was supported by Alzheimers Research UK and Alzheimer’s Society through their funding of the Manchester Brain Bank under the Brains for Dementia Research (BDR) initiative. Nancy Allen did immunohistochemistry, all microscopical assessments and data analysis, and helped with paper writing.

Andrew Robinson prepared sections for staining and immunohistochemistry. Julie Snowden helped with statistical advice and clinical data. Yvonne Davidson provided technical support and training. David Mann provided study design, supervision and wrote the paper. “
“Primitive polar spongioblastoma Selleck NVP-AUY922 was first described by Russell and Cairns in 1947. However, the polar spongioblastoma pattern is often seen in many neuroepithelial tumors, and this category was deleted in the previous World Health Organization (WHO) classification. In 2010, Nagaishi et al. reported on a case involving a neuroepithelial

tumor with the typical histological pattern of polar spongioblastoma and suggested that this tumor might Alpelisib not be suited to any of the neuroepithelial tumors in the current WHO classification. We report on an autopsy case involving an unclassified high-grade glioma with polar spongioblastoma pattern that was very similar to the case described by Nagaishi et al. A 44-year-old man who presented with a headache exhibited a tumor of the right frontal lobe on MRI. Histological diagnosis of the tumor obtained by gross total resection was high-grade glioma, which was composed of the parallel palisading of spindle tumor cells expressing

GFAP, without microvascular proliferation (MVP) and necrosis. Conventional chemoradiotherapy was performed, but the case was complicated by cerebrospinal fluid (CSF) dissemination that resulted in multiple extraneural metastases through systemic diversionary CSF shunting. Finally, the patient died approximately 13 months after the initial treatment. Both the cerebral and Douglas pouch tumors that were obtained at autopsy were diagnosed as typical glioblastomas, and they were composed of the proliferation of atypical astrocytes with MVP and pseudopalisading necrosis without the formation of rhythmic palisading. Although Fossariinae the histological findings were different from that of the first operation, immunohistochemical and genetic profiles demonstrated almost the same results. This tumor was not classified as a typical glioblastoma by the initial findings, but it had the nature of a glioblastoma. These findings suggest that the tumor might be classified as a new subset of glioblastoma called glioblastoma with polar spongioblastoma pattern. “
“The effect of combustion smoke inhalation on the respiratory system is widely reported but its effects on the central nervous system remain unclear. Here, we aimed to determine the effects of smoke inhalation on the cerebellum and hippocampus which are areas vulnerable to hypoxia injury.

albicans, and T. cruzi infections demonstrate that the entrance of peripheral B and T cells into the thymus, rather than being a pathogen-specific phenomenon is

the consequence of an acute inflammatory process triggered by an early Gefitinib cell line production of the Th1 cytokines IL-12 and IL-18. One concern we needed to address is whether or not activated (CD44hi) cells or also naïve T cells are able to reach the thymus in these inflammatory conditions. To examine this question, we adoptively transferred splenocytes from a normal uninfected mouse to a T. cruzi infected mouse and evaluated phenotype of the cells that entered to the thymus. We observed that they are CD44int/hi and CD62Lhi despite the fact that the cells expressed lower levels of CD44 and CD62L before the injection (not shown). Thus, we concluded that because we inject naïve cells into recipient mice that are actively expressing high levels of inflammatory cytokines, naïve cells get activated themselves during the 18 h they reside into the recipient mice. These data support the fact

that only cells with an activated phenotype and expressing CD62L are able to reach the thymus in the context of these inflammatory conditions. Even though we do not describe here what subset of peripheral leukocytes could migrate to the thymus in situations when IL-12 and IL-18 are systemically expressed, it is interesting to note that other investigators selleck compound have characterized a subset of splenic CD44hi CD8+ T cells that, in the presence of both IL-12 and IL-18, can rapidly secrete IFN-γ in the absence of specific Ag [36, 37]. In vivo, the activation of these cells is triggered by different pathogens such as Listeria monocytogenes [36] or during certain acute viral infections [22]. Based on these reports and our own data with OVA-transgenic mice

that demonstrate that T cells that enter the thymus are not exclusively clones activated by Ags expressed by the pathogen itself, we speculate that in a normal nonimmunized mouse there exists a subset of B and T cells that are able to rapidly respond to IL-12 and IL-18 (or to cytokines induced thereafter), become activated and acquire the capacity to migrate back to the cAMP thymus. We still need to determine if these cells originate from the preexisting CD44hi pool or if they derive from naïve CD44lo cells that somehow get activated and upregulate CD44, CD62L, and CCR2 in the presence of inflammatory cytokines and these studies will be the focus of future research. Even though most of the reports that evaluate migration of cells to the thymus use the i.v. route [6-8, 16, 17], we also performed adoptive transfer experiments with splenocytes stained with CFSE and injected i.p. (not shown in this manuscript) and demonstrate that in this case, utilizing a different route other than the bloodstream, peripheral cells migrate in similar proportion to the thymus as when cells were injected intravenously.

Results  When compared to the

post-partum samples, significant pregnancy-related changes in IFNγ, TNFα, VEGF, GCSF, Eotaxin, and MCP-1 expression were observed. These changes have significant immunologic effects in vivo and in culture. Conclusion  Pregnancy-associated changes to steady state serum cytokines may have important immunologic consequence. “
“We studied early NK-cell recovery in 29 allografted patients undergoing different lymphoreductive regimens. Already at 2 wk after graft take, the number of NK cells had buy RG-7388 reached (supra)normal levels but NK-cell subsets were skewed. The number of CD56dimCD16bright NK cells was low and correlated strongly with the level of hematopoiesis, whereas the number of the more abundant NK cells expressing high levels of CD56 did not. Post-transplant CD56bright NK cells (ptCD56bright) differed from CD56bright NK cells in normal controls (CD56bright) in being HLA-DR- and perforin-positive, CCR7−, CD27−, CD127− and mostly

c-kit−. CD56bright from normal controls stimulated by IL-15 in vitro (NKIL-15) acquired all the characteristics GSK1120212 clinical trial distinguishing CD56bright from ptCD56bright. IL-2 exerted similar effects. Moreover, when cultured without cytokines, ptCD56bright, CD56bright and NKIL-15 responded similarly by upregulating CD127 and c-kit but not CCR7. IL-12 stimulated IFN-γ production in ptCD56bright, whereas CD56bright responded only to IL-12 plus IL-15. Hence, ptCD56bright have all the features of cytokine-stimulated CD56bright. Because only patients with low numbers of T cells had high numbers of ptCD56bright, we conclude that ptCD56bright are activated CD56bright that expand while competing with T cells for the elevated post-transplant level of IL-15. In humans, most lymphocytes without Carnitine palmitoyltransferase II rearranged antigen-receptors express CD56 and are referred to as NK cells. Accordingly, they can be identified on the basis of a CD3−CD56+ phenotype 1–3, which excludes the subpopulation of T cells that coexpress CD56. However, this long-established definition of NK cells may be inadequate because CD3−CD56+ lymphocytes

are heterogeneous and capable of exerting various effector functions other than killing cells with altered expression of self-MHC. Furthermore, many CD3−CD56+ lymphocytes do not lyse NK-cell targets when tested ex vivo and only acquire lytic activity after in vitro stimulation with cytokines. In fact, the large granular CD3−CD56+ lymphocytes with “natural” cytotoxicity that express low levels of CD56 (CD56dim) and high levels of the Fcγ-receptor type III (CD16) 1–4 represent only a minority of all of the CD3−CD56+ lymphocytes in the body 5, 6. CD56dim that provide first-line defense against viruses 7, 8 make out 90% of NK cells in human peripheral blood. They express killer immunoglobulin-like receptors (KIR), contain perforin and granzymes and are considered to be end-stage cytotoxic effector cells. A substantial percentage of CD56dim lacks CD94 4.

Finally, we integrate all of these findings to gain an overall picture of the mechanism of epileptogenicity. Acquisition of temporally sequential images facilitates three-dimensional analysis of neuronal activity propagation. Previously, we have investigated neocortical tissues learn more that were considered clinically to be the secondary epileptogenic focus, and reported unique propagation of neural activity within the cortical slices.[5] We found that the elicited neural activities spread horizontally along the layers momentarily in the epileptogenic cortex, although they were not observed in control brain tissues taken

from patients with brain tumors who had no history of epileptic episodes before surgery (Fig. 5). The characteristic propagation comprises two spatially and temporally unique components: the identically shaped early phase and the polysynaptic late phase. Furthermore, we observed neuronal hypertrophy, loss of dendritic spines, and nodular varicosities

of dendrites, which might participate in the aberrant activities observed by flavoprotein fluorescence imaging. Optical imaging is a powerful approach for investigating local neuronal networks in the epileptogenic focus. Previous animal studies using optical imaging in vitro have revealed the topological relationship between the stimulated area and functionally connected area, whereas both areas are topologically apart, such as the thalamus and primary Akt inhibitor somatosenseory cortex.[12, 13] By applying this type of analysis to human brain slices, we have observed functional connections between heterotopic nodules and the overlying hippocampus.[6] Slices were prepared from the temporal lobe of a 22-year-old man with periventricular nodular heterotopia, who manifested intractable mesial temporal lobe epilepsy. Microscopically, multiple heterotopic nodules were observed adjacent to the subiculum of the hippocampus. We electrically stimulated the incubated slices, and the elicited neural activity was analyzed as changes in flavoprotein fluorescence signals. When we stimulated either the heterotopic

nodule or the overlying hippocampus, clear functional coupling of neural activity between these structures was observed (Fig. 6). Interestingly, click here the functional coupling activities evoked in either the heterotopic nodules or the subiculum showed marked differences in terms of the pharmacological effects of bicuculline. Moreover, using Western blotting, we detected the expression of both NR1 and NR2 (NMDA receptor subunits) in the heterotopic nodules, although at a lower level than in the subiculum. Thus, it seems likely that the excitatory connections between heterotopic nodules and the subiculum involve different mechanisms. Application of the flavoprotein fluorescence imaging technique to human brain slices is useful for investigating the pathomechanisms underlying epileptogenicity.

We hope for continuous EFIS-EJI support for future meetings, which is indispensable as it provides travel grants for a significant number of young immunologists who attend the conference. The next conference is planned for September 2012 and the details will be posted on http://www.img.cas.cz/tatra/ approximately one year in advance of the meeting. Perhaps we will see you there. Radek Špíšek Department of Immunology, Charles University, 2nd Faculty of Medicine, University Hospital Motol, Prague, Czech Republic e-mail: [email protected]

“
“The behavior of self-reactive T cells mTOR inhibitor in the peripheral immune system has often been studied by following the fate of adoptively transferred antigen-specific T cells in antigen expressing mice. In most cases, after a period of expansion, such cells undergo a slow clonal deletion, accompanied by the onset of anergy and/or suppression in the remaining cells. Here, we demonstrate that at initial frequencies approaching those found in normal repertoires, it is possible to completely avoid deletion Target Selective Inhibitor Library and still maintain peripheral tolerance. At starting numbers of <1000 T cells, stimulation by chronic self-antigens resulted in a period of robust clonal expansion, followed by a steady plateau phase extending

beyond 4 months. Despite their Selleckchem Gemcitabine stable persistence, the self-reactive T cells did not convert to a Foxp3+ fate. However, they displayed a considerable block in their ability to make IL-2, consistent with the onset of anergy — in a precursor frequency or deletion independent fashion. In an adaptive immune repertoire, the frequency of T cells that are specific for any given pathogen is thought to be very low. Although the precise numbers are difficult to estimate, in the mouse, it is thought to range in frequency from 1/1000 to 1/100,000 [1, 2] and numerically as low as 20 per mouse [3, 4]. The robust clonal expansion and differentiation that follows antigen recognition in vivo, is therefore geared to expanding

these rare precursors to large numbers of potent effector cells, in a short amount of time. However, the same process can be lethal if the target epitope is derived from a self-antigen. Therefore, the vertebrate has evolved several processes to curtail self-reactive T cells. After central tolerance deletes a large proportion of these, very few escape to the periphery. This makes it even more difficult to isolate and follow their behavior in unmanipulated animals (until an autoimmune process activates and expands them). Instead, we and others have routinely used adoptive transfer model systems that infuse a traceable population of self-reactive T cells into mice and follow their fate.