1) at ETS/IRF composite elements (EICE), description of AP-1/IRF composite elements (AICE) reveals how these factors function together to bind distinct elements

co-operatively, and may explain some of their distinct functions in T-cell subsets, dendritic cells and B cells. At AICE, combinatorial integration is possible through both varied AP-1 dimer composition and choice of IRF family co-factors. For example, IRF8 co-operates with BATF3/JUN to instruct homeostatic classical dendritic cell (cDC) differentiation, and with BATF/JUN during inflammatory cDC differentiation.[40] BATF/JUN and IRF4 co-operative binding at AICE motifs is required for instruction of Th17 HSP inhibitor differentiation and B-cell class switch recombination.[12,

30, 31, 40] Further, it is likely that co-operation of these AP-1/IRF complexes with different STAT family members can confer additional integration of environmental cues for interpretation of combinatorial motifs in regulatory DNA elements. Transcriptional programmes that integrate environmental signals with cell intrinsic features instruct cellular phenotypes, including plasticity. In this context, it is interesting to compare and contrast the transcriptional strategies of FOXP3 and RORγt in control of Treg and Th17 cell identity, respectively. Recent mechanistic insights into the transcriptional regulation of Foxp3 and Rorc and their targets explain some of the characteristics of the Treg and Th17 cellular phenotype. For example, both FOXP3 and RORγt have in common an activity that largely reinforces, stabilizes and maintains a chromatin Alpelisib and gene activation landscape initiated

by ERFs. More specifically, these factors augment the expression of critical lineage-specific genes such as il2ra, ctla4, il10, il10ra, cd5, icos and notably, Foxp3 itself, in the case of FOXP3, and il17a, il17f, il1r1 and il23r for RORγt (Fig. 1). This target gene selection reflects the distinct behaviour and biology of Th17 and Treg cells. RORγt augments il23r expression in a positive feedback loop, as STAT3 signalling downstream of IL-23R activates Rorc expression. However, this feedback loop, and maintained expression Fossariinae of Rorc and Th17 lineage fidelity, is dependent on the persistence of environmental IL-23 and transforming growth factor-β (TGF-β), and altered environmental signals, especially IL-12 and interferon-γ, can subvert Rorc expression and the Th17 transcriptional programme, converting cells to the Th1 lineage (Fig. 2).[42-44] In contrast, FOXP3 regulates its own expression upon engagement of a positive feedback loop following activation and CpG demethylation at a Foxp3-intronic enhancer (CNS2), a heritable feature of mature Treg cells, effectively buffering mature Treg cells from changes in environmental signals.[45] These differences may reflect important phenotypic features of these distinct cell types.

The importance of IL-23 in the development of numerous autoimmune diseases (summarized in Fig. 2) has buy SB203580 by now been established, but the fact that naïve T cells do not express il23r raises questions about the upstream signaling events that render T cells sensitive to IL-23 at later stages. This mechanism of action is similar to IL-18, which also does not act on naïve T cells lacking the necessary receptors to sense its presence [28, 32]. It seems that IL-23R expression on T cells is induced first after activation in the presence of IL-21 [33, 34], a STAT3-dependent cytokine. IL-21 is abundantly expressed

by T cells activated in the presence of IL-6 [35, 36], which is likely provided by activated dendritic cells and macrophages in vivo. As such, the signals provided by APC-derived IL-6 are crucial at the moment of T-cell activation, conferring responsiveness to IL-23. One could reason that mice LDE225 molecular weight lacking IL-21 or its receptor may well phenocopy p19−/− mice

if IL-21 was essential for IL-23R expression. Interestingly, IL-21 signaling is not required for EAE induction [37], but IL-23 is an absolute necessity [25]. These findings collectively imply that IL-21-independent mechanisms of IL-23R expression exist in vivo. However, sustained IL-23 signaling on T cells seems to be of importance for maintaining inflammation. For example, during the recovery phase of EAE, reduced levels of IL-23 expression were observed in draining lymph node-derived DCs [38]. This reduction also mirrored a drop in T-cell-derived IL-17, which points Bay 11-7085 to a correlation between the cessation of IL-23 expression and recovery from disease associated with reduced pathogenic T-cell generation and/or activity. Blockade of IL-23 in the clinical setting is now receiving substantial attention after the rapid accumulation of studies highlighting the essential role of IL-23 in so many animal models of inflammation. The connection between IL-23 and autoimmune disease in humans is supported by evidence showing that polymorphisms in the il23r locus are linked to Crohn’s disease and psoriasis

(reviewed in [39]). Interestingly, a recent gene association study looking at multiple sclerosis highlighted a number of immune related genes for this disease, but not IL-23 nor IL-23R [40]. A major advantage of IL-23 as a therapeutic target is that it appears to be effectively inhibited in vivo by monoclonal antibodies and some pharmacological inhibitors of IL-12/23 subunit expression. Ustekinumab is a human monoclonal IgG1 antibody, which binds the p40 subunit and prevents functional IL-12 and/or IL-23 from interacting with IL-12Rβ1. This inhibitory activity blocks downstream events of both the IL-12 and IL-23 signaling cascade [41]. Two recent clinical trials showed that patients with severe psoriasis benefited significantly from a treatment course with ustekinumab, according to the psoriasis area and severity index (PASI) criteria [42, 43].

p. bakeri [31, 58, 59]. Already data had been provided that in contrast to the majority of popular laboratory mouse strains, LAF1 mice lost worms within 3 weeks of infection [60] and SJL were capable of expelling primary infections with H. p. bakeri within 6–11 weeks of oral infection [58, 61]. Another strain that was also found to be capable of eliminating primary infection worms rapidly was SWR [62]. Many different strains were ranked in terms of

their capacity to resist primary infections and to express acquired resistance [31, 63, 64, 15], and therefore, it was possible now to correlate antibody responses CP-690550 order with resistance across mouse strains of varying genotype and responder phenotype. Much as expected, it was soon found that good responder strains produced high levels of parasite-specific IgG1, and poor responders much lower [59, 64, 15], and even within the strong/intermediate responder strains, IgG1 levels correlated

negatively with worm burdens [65]. Until now, most work on H. p. bakeri has made use of polyclonal Abs (particularly IgG1) purified from infection/vaccination sera in neutralization tests in vitro and in vivo. These experiments are technically demanding and far from optimal as sera contain a mixture of antibody isotypes, HER2 inhibitor some with inappropriate specificities (such as blocking antibodies) and the potential selleck inhibitor to trigger inhibitory signals through immunoreceptor tyrosine-based inhibition (ITIM) motifs. It is difficult to ensure the absolute purity of such antibodies, and minor contamination with a highly biologically active isotype may give misleading results. Purifying antibodies from small volumes of mouse sera is time-consuming and results in small yields that are difficult to standardize. Furthermore, antigen-directed, isotype restriction

means that different subclasses will not recognize identical epitope populations. As epitope density has a major influence on the efficiency of effector mechanisms, such as antibody-dependent cellular cytoadherence (ADCC), it has been virtually impossible to determine whether a particular result is representative of the fundamental role played by IgG1. One way forward in achieving a deeper understanding of the precise role of antibodies in H. p. bakeri infection will be to engineer recombinant epitope-matched monoclonal antibodies for each IgG class with which to dissect their function without fear of contamination from other antibody types or other serum components that co-purify on protein G/A columns, as has been done recently in the case of malaria [66, 67]. The last three decades, since the start of the 1990s, have seen an unprecedented pace of change and advances in technologies in biology. Parasite immunologists working with H. p.

The catheter isolate was chosen from the collection of catheter isolates (Department of Microbiology and Virology) because of its high biofilm production (H. Bujdáková, unpublished data). The C. albicans CR3-RP has been already noted as being involved in adhesion to buccal epithelial cells. Additionally, preliminary experiments suggested that blocking this antigen resulted in a decrease selleck inhibitor in the biofilm (Bujdákováet al., 2008). To confirm the hypothesis about CR3-RP participation in the adhesion process, it was necessary to prove that this antigen is expressed in the biofilm. Three different experiments were carried out to confirm the expression of the CR3-RP antigen in the adhesion phase

as well as in mature biofilm. The polyclonal anti-CR3-RP antibody was prepared according to the peptide sequence of CR3-RP (Bujdákováet al., 2008). The already characterized OKM1 mAb

(former iC3b-like protein, Bujdákováet al., 1999) was also used in every experiment. Figure 1 (left) documents the strong immunofluorescence when using anti-CR3-RP antibody in C. albicans CCY 29-3-162 in a mature biofilm. The reaction with OKM1 mAb was lower (Fig. 1, left, despite lower dilution – 1 : 10), but it must be kept in mind that this antibody only cross-reacts RG7420 cost with the C. albicans antigen. The results from immunocytometry (Fig. 2) were in agreement with those observed in fluorescence microscopy; the detection of the CR3-RP using polyclonal anti-CR3-RP antibody was higher than with OKM1 mAb. Moreover, the evaluated samples could be categorized according to the morphology of the yeasts, the budding yeasts or small hyphae, and the long

hyphae (FSC and SSC distribution). The fluorescence signal was detected in all morphological forms with strong expression in the hyphae and a weaker expression in the yeasts or germ tubes. Additionally, the difference between the anti-CR3-RP antibody and OKM1 mAb signals Farnesyltransferase showed the higher specificity and potency of the polyclonal antibody to interact with the CR3-RP antigen. A similar result was observed with the catheter isolate (data not shown). The quantification of the total CR3-RP expression was performed using ELISA in both C. albicans strains. In this experiment, the CR3-RP was detected in adherence phase (90 min) as well as in the mature (48 h) biofilm. Figure 3 documents that CR3-RP is manifested in both phases of the biofilm. Of course, the expression of this antigen is markedly higher in the mature biofilm because of the presence of the hyphal morphological form, which has, however, already been proved to be expressed in a higher quantity than the yeast form (Bujdákováet al., 1999). It has been already proposed that the adhesion phase is the key step affecting the whole process of biofilm formation (Chandra et al., 2001; Nobile et al., 2008; Soll, 2008).

, 2004; Mulvey et al., 2005; David et al., 2008; Van De Griend et al., 2009). Recent studies show that USA400 can account for over 98% of MRSA infections in northern Canada (Golding et al., 2011) and has been implicated in isolated Metformin MRSA disease in southern Europe (Vignaroli, 2009; Neocleous et al., 2010). However, about 10 years ago, a new source of CA-MRSA arose from one of the ‘traditional’ virulent CCs, CC8. Descending from a USA500

clone through acquisition of various MGEs (Robinson & Enright, 2003; Li et al., 2009), USA300 became the dominant CA-MRSA clone in US (Moran et al., 2006; Hulten et al., 2010; Talan et al., 2011), effectively replacing USA400 clones in most regions (Como-Sabetti et al., 2009; Simor et al., 2010), and has also been isolated from patients in Canada and Mexico (Nichol BMN673 et al., 2011; Velazquez-Meza et al., 2011).

The explosion of USA300 CA-MRSA across North America resulted from a very recent clonal expansion of a successful CA-MRSA clone as demonstrated by very low sequence divergence among geographically distinct USA300 isolates (Kennedy et al., 2008). Given the occurrence of multiple CA-MRSA clones in the population, a formal definition was put forth by the Center for Disease Control and Prevention for CA-MRSA disease as that which is contracted within 48 h of hospital admission by patients not having recently undergone surgery, hemodialysis, prolonged hospitalization, Venetoclax clinical trial catheterization, or MRSA colonization (Morrison et al., 2006). Currently in the US, MRSA disease fitting these criteria is almost always caused by USA300 clones, followed by USA400 and occasionally USA1000 and USA1100 (Talan et al., 2011). To complicate matters further, USA300 clones have recently been implicated in causing significant HA-MRSA disease (Popovich et al., 2008; Jenkins et al., 2009; Moore et al., 2009; Hulten et al., 2010), blurring the lines between the two disease

onset environments (Popovich et al., 2008; Jenkins et al., 2009; Moore et al., 2009; Hulten et al., 2010). In some studies, USA300 accounted for at least half of hospital-acquired MRSA infections (Popovich et al., 2008; Hulten et al., 2010). Thus, USA300 represents a highly successful S. aureus clone that emerged in the community and quickly spread throughout the North American continent to become the leading cause of MRSA infection even in healthcare settings. For now, USA300 seems to be primarily limited to North America, while in Europe, South America and Asia, CA-MRSA disease is dominated by divergent clones unrelated to CC8 (e.g. ST30, ST80 and ST59) (Deleo et al., 2010). Given the rapid and efficient transmissibility of USA300 in North America (Pan et al., 2005), it remains to be seen whether these clones will become the dominant source of MRSA disease worldwide. Animal models of S.

Thus, this study was undertaken to further investigate the efficacy of INCB024360 in vitro recNcPDI vaccination employing both CT and CTB as adjuvants, and application of corresponding emulsions via the intranasal route. In addition, both antigen formulations were assessed in

the pregnant mouse model to investigate the capacity of recNcPDI to limit foetal Infection. Besides assessing the splenic transcript levels of classical Th1 (IL-12, IFN-γ) and Th2 (IL-4, IL-10) cytokines upon challenge, we also investigated expression levels of the proinflammatory cytokine IL-17 and the transcription factor Foxp3, a marker for T regulatory (Treg) cell activation, both of which are implicated in immune regulation of Inflammatory responses during pregnancy. Unless otherwise stated, all cell culture reagents were supplied BYL719 in vivo by Gibco-BRL (Zurich, Switzerland), and chemicals were purchased from Sigma (St. Louis, MO, USA). Neospora

caninum tachyzoites of the Nc-1 isolate [23] were propagated by serial passages in Vero cells. Purified tachyzoites were obtained and counted [24]. Recombinant PDI (recNcPDI) was cloned into the His-tag expression vector pET151 and expressed in Escherichia coli BL21 Star and purified (Invitrogen, Zug, Switzerland) [17]. The protein concentration was measured with the Bio-Rad protein assay. Following dialysis into PBS, recNcPDI was stored at −20°C. Animal procedures were approved by the animal welfare committee of the Canton of Bern and followed the corresponding guidelines. All Balb/c

mice (females, 9 weeks of age) purchased from Charles River Laboratories (Sulzheim, Germany) were checked serologically for the absence of anti-N. caninum IgG by ELISA. Eighty five females were randomly divided into Branched chain aminotransferase five groups of 17 animals each (Table 1). The vaccination (three doses at 2-week intervals) was done by intranasal (i.n.) application through the nares under mild isoflurane anaesthesia [17]. Mice in group 1 (PBS) received sterile PBS only, group 2 (CT) received 0·5 μg CT, group 3 (CT-PDI) received 10 μg of recNcPDI emulsified in 0·5 μg CT, group 4 (CTB) received 0·5 μg CTB and group 5 (CTB-PDI) received 10 μg of recNcPDI in 0·5 μg CTB. Mating and gestation were carried out as previously described [25-27]. Females were challenged at day 7 post-mating by i.p. inoculation of 2 × 106 N. caninum tachyzoites. At day 19 post-mating, pregnant and nonpregnant mice were separated, and pregnant mice were housed separately to rear their pups. All mice were inspected daily throughout the experiment for clinical signs of neosporosis (ruffled coat, apathy, hind limb paralysis, rounded back and circular movements) using a standardized score sheet and were killed when clinical signs were evident. Adult mice were weighed at 3-day intervals from 3 days prior to the first vaccination; neonates were weighed from day 14 post-partum until the time of euthanasia.

Most efforts in characterizing HLA-DQ binding specificities have been directed towards a few selected molecules, such as DQA1*05:01-DQB1*02:01 (also known as DQ2) or DQA1*03:01-DQB1*03:02 (DQ8) because of their association with disease.19–21 The data published by Wang et al.7 aim to be more comprehensive in terms of human population coverage, and they include binding data for the six most common allelic BYL719 variants across different ethnicities. The HLA-DQ sequence motifs identified by NNAlign are shown in Fig. 2. In contrast to the DP variants, which appear

to share a common supertypical pattern, the DQ molecules show very little overlap in specificity. There do not appear to be common amino acid preferences, and the anchors are found at different positions within the 9-mer core. In particular, DQA1*01:01-DQB1*05:01 shows a strong preference for aromatic residues (F, W, Y) at P5, and secondary anchors at P6 and P7. The only previous report addressing the binding motif of this molecule8 also found a dominant

anchor characterized by a preference for W and F, but placed this anchor at P4, and is generally in disagreement with our findings on other positions. The binding motif for DQA1*01:02-DQB1*06:02 appears loose, with several amino acids allowed at most positions. Previous reports22,23 identified mainly a P4–P6–P9 anchor spacing, with small and hydrophobic GW572016 residues at P4, hydrophobic/aliphatic amino acids such as I, L, M, V at P6, and small residues like A and S at P9. Similar amino acid preferences are reflected in the binding motif detected Buspirone HCl by NNAlign, with additional anchors at P3 and P7. The only pair of molecules that appear to have a somewhat similar specificity is composed of DQA1*03:01-DQB1*03:02 and DQA1*04:01-DQB1*04:02. Both show a dominant anchor at P9, with preference for the acidic residues E and D. Additionally, they both show a preference for hydrophobic amino acids at P6, and mainly for A or E at P8. The strong acidic anchor at P9 was observed before.19,24 In the case of DQA1*05:01-DQB1*02:01, previous studies describe

a motif with P1 and P9 binding pockets with hydrophobic/aromatic preferences, and acidic residues in the centre of the core, particularly at P4, P6 and P7.8,24–28 Besides the hydrophobic/aromatic P1–P9, NNAlign places the strongest anchor at P7, but with preferences for glutamic acid (E) also at P6 and P8. Finally, the somewhat peculiar sequence motif of DQA1*05:01-DQB1*03:01 seems to just prefer small amino acids such as A, G and S, especially on the central positions of the core, in agreement with the motif previously suggested for this molecule.8 It is evident that the peptide-binding specificities for HLA-DQ variants are much more diverse than for HLA-DP variants. In particular, the strong hydrophobic/aromatic P1 anchor that generally characterizes all known HLA-DR and DP molecules is not observed here.

In contrast to oestradiol, raloxifene did not have the capacity to ameliorate the effector phase of arthritis. We also report that the induction of CAIA, by itself, did not induce osteoporosis. Interestingly, both raloxifene and oestradiol prevented LPS-induced trabecular bone loss. Additional experiments are needed to elucidate the mechanisms whereby oestradiol and raloxifene exert their beneficial effects on arthritis and inflammation-triggered osteoporosis. We thank Margareta Rosenkvist, Berit Deforolimus clinical trial Eriksson, Anette Hansevi and Maud Petersson for excellent technical assistance. This study was supported by grants from the Medical Faculty of Göteborg University

(ALF), Göteborg Medical Society, King Gustav see more V’s 80 years’ foundation, the Sahlgrenska Foundation, the NovoNordic Foundation, the Börje Dahlin foundation, the Association against Rheumatism, Reumaforskningsfond Margareta and the Swedish Research Council. The authors declare that they

have no competing interests. “
“Mutations in the signal transducer and activator of transcription 3 (STAT3) were reported to cause hyperimmunoglobulin E syndrome (HIES). The present study investigates T helper type 17 (Th17) responses triggered by the relevant stimuli Staphylococcus aureus and Candidia albicans in five ‘classical’ HIES patients, and a family with three patients who all had a milder HIES phenotype. We demonstrate that patients with various forms of HIES have different defects in their Th17 response to S. aureus and C. albicans, and this is in line with the clinical features of the disease. Interestingly, a partial deficiency of interleukin (IL)-17 production, even when associated with STAT3 mutations, leads to a milder

Adenosine clinical phenotype. We also observed defective Th17 responses in patients with the ‘classical’ presentation of the disease but without STAT3 mutations. These data demonstrate that defective IL-17 production in response to specific pathogens can differ between patients with HIES and that the extent of the defective Th17 response determines their clinical phenotype. Hyperimmunoglobulin E syndrome (HIES) is a primary immunodeficiency disorder characterized by recurrent staphylococcal skin abscesses, pulmonary infections, mucocutaneous candidiasis, skeletal and dental abnormalities and elevated serum immunoglobulin E (IgE) concentrations [1,2]. Although most cases of HIES are sporadic, familial cases are encountered, mainly with an autosomal dominant mode of inheritance [3]. Recently, mutations in the evolutionarily conserved SH2 and DNA-binding domains of the signal transducer and activator of transcription 3 (STAT 3) were found to be present in approximately 60% of the patients with HIES [4,5].

4 mM of AC-

or BC-primer and 0.4 mM of AV- or BV-specific primer. After an initial denaturation step of 10 min at 94°C, the reactions were subjected to 40 cycles of PCR (94°C selleck chemicals for 30 s, 58°C for 40 s, 72°C for 50 s), followed by a final extension step of 5 min at 72°C. Runoff products were purified using Sephadex gel and filter plates (Multiscreen, Millipore, Billerica, MA, USA) before they were sequenced using fluorescent chain-terminating inhibitors (BigDye Terminator v1.1 kit) and an automated capillary sequencer (ABI Prism 3700 DNA Analyzer, Applied Biosystems). CDR3α and CDR3β definitions as well as AV and BV nomenclature are according to IMGT (http://imgt.cines.fr). Cytokines were selected for cluster analysis on the basis of their recognized contribution to characterize both known and potential CD4+ T-cell subsets. Cytokine secretion levels of PMA and calcium ionophore-activated CD4+ T cells were determined ex vivo at the single-cell level using a BD LSRII apparatus. Fluorescence intensity values were directly extracted from the corresponding Flow Cytometry Standard (FCS) files

using Flow Cytometry Standard Extract Utility (Earl F. Glynn, Stowers Institute for Medical Research, KS, USA) and analyzed using Ward’s method (see below). T-cell clone clustering was based on cytokine ELISA measurements in culture supernatants. In that case, the molar concentration of each cytokine measured was expressed as the percentage of the six measured cytokines produced by a given

SB203580 supplier T-cell clone and normalized in order to express results independently of their measurement scale. Agglomerative hierarchical cluster analysis according to Ward’s 46 was performed using SDHB the JMP7 software (SAS Software, NC, USA). The optimal number of clusters was identified according to the largest distance change between successive junctions of the dendrogram plot. Validity and reproducibility of the classification obtained with hierarchical cluster analysis was assessed using non-hierarchical k-means cluster analysis, in which the optimal number of clusters identified through hierarchical cluster analysis was pre-specified. Reproducibility of the classifications obtained with both hierarchical and non-hierarchical clustering was assessed by determination of the kappa value. Differences between groups and clusters were tested using Mann-Whitney U-test (unpaired), Wilcoxon signed rank test (paired) and Kruskal-Wallis test. All tests were two-sided and a p-value <0.05 was considered statistically significant. This study was supported by Inserm, by the Centre d’Investigations Biologiques (C.I.B.) Pitié-Salpêtrière, by the Université Pierre et Marie Curie “EMERGENCE” program and by the European FP6 “ATTACK” program (Contract: LSHC-CT-2005-018914).Authorship contributions: M.L., M.H., D.D., C.P., J.P., K.D., M.S. and D.S. performed research, J.P., H.Y., and L.A. contributed vital new reagents and analytical tool, S.B., M.K. and Z.A.

Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by Galunisertib the authors. “
“Cohn M. Meanderings into the regulation of effector class by the immune system: derivation of the trauma model. Scand J Immunol 2012;76:77–88 delves into the discussion of how the immune system might regulate the decision

between the immune response effector classes, and in particular identifies some key questions that need to be asked to understand how different classes of immune response occurring at the same time might be able to remain coherent and discrete. This is a needed discussion that advances the field, and the experiments proposed will go a long way to Protease Inhibitor Library ic50 increasing our understanding of effector class regulation. However, in my opinion, the author makes some strong statements requiring substantiation regarding the impossibility of the involvement of germline-selected recognitive events as participating in self/non-self discrimination. Furthermore, the present discussion ignores a large body of contemporary

literature describing the function and specificity of FoxP3+ regulatory T cells (Treg) and formulates a theory that specifically excludes a role for Treg in maintaining self-tolerance without placing the contemporary evidence in the context of that theory. Thus in my opinion, these shortcomings should be addressed by the author. 1. A self and non-self selection process mediated by a somatic historical process is clearly involved in the sorting of the T cell repertoire into anti-self (which are eliminated or converted to natural Treg) or anti-non-self. However it is not clear to me how one can use this to validly exclude germline-selected recognitive events, as proposed by the danger model for example, from also playing a complementary click here role in S and NS discrimination in the periphery. Evolutionarily speaking, some

level of self-reactivity escaping ‘Module 2’ into the peripheral T cell repertoire may have conferred a fitness advantage through the enhancement of, for example, anti-tumour immunity. Thymic negative selection clearly does not eliminate all self-reactive immature Th cells from the repertoire, as one can find such cells in normal individuals without concomitant pathology [1, 2]. This fact also implies that there is some threshold number of self-reactive Th cells below which no adverse effect occurs, and thus, we must consider quantitative as well as qualitative aspects when considering what makes up the T cell repertoire. Instead of viewing the T cell ‘repertoire’ as just the set of individual T cell clones that are present in an individual, if one adds the dimension of how many of each of a specific T cell clone there are, then the control of expansion of a particular T cell clone becomes a way to shape the ‘effective repertoire’.