Adoptive transfer of TCR transgenic T cells specific for LCMV, followed by infection with the chronic strain of the virus, led to clonal deletion of the transferred

cells. However, prior to deletion, the transferred cells were found to lose cytotoxic activity. The chronic viral infection ‘exhausted’ the T-cell adaptive immune response by both clonal deletion and anergy of effector function [4]. The advent of tetramer technology made possible the further refinement of the definition of this process. Detection of Ag-specific cells by tetramers demonstrated that Ivacaftor order not all clones are deleted in response to chronic LCMV. Thus, the term exhaustion was refined to describe the remaining Ag-specific population with diminished effector function, as measured by CTL activity and the secretion GDC-0941 mw of IFN-γ [5, 6]. The significance of this exhausted population in human chronic viral infections was subsequently confirmed by the finding that the inhibitory receptor PD-1 marked exhausted cells with diminished proliferative capacity in HIV infection [7]. In order to investigate the transcriptional control of the exhausted phenotype, investigators carried out differential gene expression analysis by microarray of exhausted

versus other Ag-specific populations induced by LCMV. From this analysis, it was discovered that the transcriptional repressor, Blimp-1, was significantly upregulated in the exhausted population [8]. The role of Blimp-1 was first defined in the B lymphocyte, where it plays a vital role in terminal differentiation [9]. The finding that Blimp-1 was expressed in CD8+ T cells [10, 11] prompted investigators to search for a similar role for Blimp-1 within CD8+ T cells. Two independent groups demonstrated that, in response to viral challenge, responding Blimp-1-deficient CD8+ T cells had lower percentages of cells that were terminally differentiated [12, 13]. There has been less information regarding the role of Blimp-1 in murine CD4+ T lymphocytes, though similar attenuation of

in vivo proliferative responses has been observed [14]. In order to determine the role that senescence-associated Blimp-1 C59 order has in viral-induced T-cell exhaustion, mice with a T-cell deficiency of Blimp-1 were challenged with chronic LCMV. Blimp-1-deficient cells were found to express, at a lower number and at a lower level, a number of the exhaustion-defining inhibitory receptors, including PD-1 [15]. Alongside its ability to control inhibitory receptor expression in chronic viral infections, Blimp-1 has effects on the other defining characteristic of exhausted T lymphocytes including cytokine production, with Blimp-1 expression being shown to prevent T-cell secretion of IL-2 and IFN-γ in CD4+ T cells [14]. The inability of HIV-exhausted T cells to secrete IL-2 and IFN-γ has been documented and is another feature of the difference between those with CHI and LTNPs [16, 17].

In addition, it has been shown that treatment with ATG is associated with the expansion of FoxP3+ T cells in vivo and suggests a shift in Treg to a Teff ratio. Despite this, CD4+ and CD8+ memory cells are resistant to depletion by ATG and these cell subsets expand

over the initial 6 months post-transplantation [73]. The fact that memory cells survive deletion may explain why patients do not suffer opportunistic infections post-ATG therapy. However, these cells can contribute PF-02341066 supplier to early graft injury and loss and, importantly, these cells are more resistant to suppression by Tregs than naive T cells [74]. However, to limit memory T cell expansion (post-induction therapy), transplant recipients are maintained on other immunosuppressive drugs, most commonly a calcineurin inhibitor (CNI) such as tacrolimus or cyclosporin A, and an

anti-proliferative agent such as mycophenolate mofetil. It has been proposed that both types of drug inhibit the generation and function of Tregs. Despite this, in animal models in the context of autoimmunity it has been shown that for Tregs to exert their suppressive function tissue inflammation needs to be controlled [75]. It seems Dabrafenib molecular weight that for Tregs to expand in vivo and exert their suppressive function they require a tolerogenic milieu. In support of this, a recent study analysing the dynamics of the alloimmune response in vivo demonstrated a rapid invasion of effector cells in the grafts followed by the delayed arrival of Tregs that were ineffective at controlling tissue damage [76]. In contrast, when the recipient mice were treated with anti-CD40L

mAb and rapamycin, effector T cell infiltration was delayed and more than 30% of the graft infiltrating T cells were Tregs. Of note, there why is good evidence in the literature indicating that rapamycin is superior to tacrolimus for the thymic export and survival of Tregs [77, 78]. In contrast to CNIs, rapamycin appears to be tolerance-permissive by selectively inducing apoptosis or necrosis of alloreactive effector cells while promoting Treg induction [79], expansion [78] and function [80]. This may suggest that rapamycin is the ideal candidate for short-term therapy post-depletion in humans. However, rapamycin monotherapy post-depletion is associated with a high risk of acute rejection [81], and it is not yet clear whether the concomitant therapy with Tregs would be sufficient to prevent this or whether further immunosuppression will be required in the short term. The use of combinations of immunosuppressive agents in the clinical setting highlight the challenge associated with designing protocols that include the infusion of Tregs. Thus, the competing actions of each immunosuppressive drug may have to be considered together with the key question of the timing of cell injection.

[8], who additionally showed that a minigene construct carrying the learn more c variant at position c.−21, when transfected to Hep G2 and Hep 3B cell lines, yielded a consistently weak RT-PCR product lacking exon 2, together with a strong full-length fragment. Nevertheless, this polymorphism is in a non-coding region of the gene and is quite rare with frequency of about 8% in heterozygotes in the general population [7–9], which could explain a more severe

phenotype in a minority of HAE patients. It seems likely that genetic factors outside of the SERPING1 gene play a substantial role as disease modifiers. Both complement and contact system activation take place in angiooedema development. Two molecules, a peptide derived from the C2 component of complement and bradykinin,

have been suspected to mediate HAE symptoms. Different lines of evidence now favour bradykinin to be the primary mediator of angiooedema [10]. Significantly selleck products increased levels of bradykinin concentration in the plasma of HAE patients during attacks were detected as compared to asymptomatic periods [11], and this difference was even more evident if the blood sample was taken from the site of oedema [12]. Moreover, another study has shown that bradykinin-mediated increase in vascular permeability in C1 Inh-deficient mice is facilitated by B2 bradykinin receptors [13]. Becasue of the evidence given previously, the B2 bradykinin receptor (BDKR2) gene was examined as one of the candidate genes, the product of which might influence the clinical manifestation of HAE [14]. A hypothesis was formulated that a polymorphic variant with a 9-bp deletion in the first exon of the BDKR2 gene, which has a higher expression in comparison with the variant without the deletion, facilitates

oedema manifestation in HAE patients [14]. However, no effect of this polymorphism on the clinical manifestation of HAE was reported in our group of patients [15]. Nevertheless, this finding does not exclude other bradykinin receptor (BDKR) genes’ polymorphisms to modify the course of the disease. The role of bradykinin B1 and B2 receptors (B1R, B2R) in the pathogenesis of other diseases has been described repeatedly [16, 17]. Another disease modifier may be the angiotensin-converting Tau-protein kinase enzyme (ACE), which is known to inactivate bradykinin. The deletion/insertion (D/I) polymorphism in the 16th exon of the angiotensin 1 converting enzyme (ACE) gene has been shown to modulate bradykinin metabolism in vivo in humans, when the D variant increased bradykinin degradation in comparison with the I variant [18]. Also relevant to our analysis, becasue of its participation in the complement activation pathway, is a potential role of mannose-binding lectin (MBL) in HAE pathogenesis. Recently, a strong correlation between MBL levels and activity of the lectin pathway was described in both HAE patients and healthy controls [19].

5A). No interaction of other mutants was partly because the mutant V proteins did not accumulate in the infected cells as revealed by immunoblotting buy SCH727965 using anti-Vu antibody (Fig. 5A, IB: αVu). The amounts of V proteins synthesized for 30 min in the presence of [35S]Cys and [35S]Met were almost equivalent to each other, although the wild-type V protein

band was faint in this gel (Fig. 5A, [35S]Cys, Met). Thus, some V mutant proteins are presumed to be unstable and easily degraded in cells. The V-R320G and V-W336G proteins appear to be stable and to accumulate in cells, while the V-W336G protein failed to interact with FL-MDA5 different from the V-R320G protein (Fig. 5A). 293T cells were transfected with p-55C1B together

with MDA5 and one of the V mutant plasmids. Cells were further transfected with poly(I:C), and proteins were metabolically labeled with [35S]Cys and [35S]Met. After 24 hr, cells were lysed and luciferase activity in the cell lysates was investigated. V proteins were then analyzed by immunoprecipitation, SDS-PAGE and an imaging analyzer, and the V protein amounts and IRF3 activation were plotted on a graph (Fig. 5B). V protein expression was almost equivalent in V-WT, V-R320G, and V-W336G. The V-WT protein suppressed IRF3 transcription activation, but V-R320G and V-W336G proteins did not. Ku-0059436 research buy These are results of one of three experiments, and results of the other two experiments showed a similar tendency. The V-R320G protein was unique in its high stability and binding capacity with the V protein. However, the binding of V-R320G

with MDA5 did not inhibit the signal induced by MDA5. SeV V protein is essential for efficient virus growth in mouse lungs and for viral pathogenicity. The V protein counteracts innate immunity that is exerted through activation of IRF3 (13). We therefore Vorinostat investigated the possibility of involvement of multiple molecules in the target of SeV V protein. A search for V-interacting molecules revealed some IRF3-activating molecules including MDA5, RIG-I, IKKɛ and IRF3 as interacting partners in a co-immunoprecipitation assay. However, the V protein only interacted with MDA5 at the Vu region, depending on the conserved cysteine residues of the Vu region. We thus focused on the interaction of the V protein with MDA5. Almost all of the SeV V mutants used in this study have 10–200-fold lower pathogenicity than that of the wild-type SeV (12). The V proteins derived from such SeV mutants did not interact with MDA5 except for V-R320G. This was due to inability of the V proteins to bind with MDA5 and, in some cases, due to instability of the V proteins in virus-infected cells. The V-R320G mutant protein was stable and interacted with MDA5 but did not inhibit IRF3 activation induced by overexpression of MDA5 and poly(I:C).

Additional features were detected in this tumor that are known to be associated with an unfavorable LY2835219 clinical trial prognosis, including loss of

p16 expression and gains of chromosomes 1q and 12. The patient experienced the most rapid downhill course reported to date for intracranial Ewing sarcoma, developing multiple extracranial metastases at 2 months and dying 6 months after the initial operation. “
“V. Leinonen, A. M. Koivisto, S. Savolainen, J. Rummukainen, A. Sutela, R. Vanninen, J. E. Jääskeläinen, H. Soininen and I. Alafuzoff (2012) Neuropathology and Applied Neurobiology38, 72–86 Post-mortem findings in 10 patients with presumed normal-pressure hydrocephalus and review of the literature Aims: Neuropathological features of idiopathic normal-pressure hydrocephalus (iNPH) are poorly characterized. Brain biopsy during life may help in the differential diagnosis of dementia, but post-mortem validation of biopsy findings is scarce. Here we review and

report brain biopsy and post-mortem neuropathological findings in patients with presumed NPH. Methods: We evaluated 10 patients initially investigated by intraventricular pressure monitoring and a frontal cortical biopsy for histological and immunohistochemical assessment find more as a diagnostic procedure for presumed NPH. Results: Out of the 10 patients, eight were shunted and seven benefited. Until death, six had developed severe and two mild cognitive impairment. One was cognitively unimpaired, and one was mentally retarded. Three subjects displayed amyloid-β (Aβ) aggregates in their frontal cortical biopsy obtained at the initial procedure. One of these patients developed Alzheimer’s disease during a follow-up time of nearly 10 years. One patient with cognitive impairment and NPH suffered from corticobasal degeneration. In six patients

Farnesyltransferase various vascular lesions were seen at the final neuropathological investigation. Five of them were cognitively impaired, and in four vascular lesions were seen sufficient in extent to be considered as causative regarding their symptoms. Conclusions: The frequent finding of vascular pathology in NPH is intriguing, suggesting that vascular alterations might be causative of cognitive impairment in a notable number of patients with NPH and dementia. Brain biopsy can be used to detect Aβ aggregates, but neuropathological characteristics of iNPH as a distinct disease still need to be discovered. “
“Wnt activation in medulloblastomas is associated with good outcome. Upfront testing and risk-adapted stratification of patients will be done in future clinical studies. In a cohort of 186 pediatric medulloblastomas our aim was to identify the optimal methods in standard clinical practice to detect this subgroup. Nuclear accumulation of ß-catenin was analyzed by immunohistochemistry (IHC). DNA of FFPE tissue was amplified by PCR for single-strand conformation polymorphism analysis and direct sequencing of CTNNB1 exon 3.

6e). To determine if xeno-GVHD resulted

from a loss of peripheral tolerance, we evaluated the levels of human Treg detectable in the blood of standard NSG–BLT mice (with irradiation) over time (Fig. 6f). The percentage of CD25+/CD127dim/FoxP3+ cells in the blood of NSG–BLT mice did not decrease over time. To determine the contribution of irradiation in the development of xeno-GVHD in BLT mice, we compared the survival of NSG–BLT mice that were either irradiated or non-irradiated (Fig. 6g). Overall, there was an increased survival of non-irradiated NSG–BLT mice; however, these animals this website ultimately developed GVHD-like symptoms. The BLT mouse, also referred to as the Thy/Liv mouse, is an ideal model to study human immune and T cell functions, as the implant of human thymic tissues and autologous human HSC enable the efficient development of HLA-restricted human CD4 and CD8 T cells [63]. Following implantation into the subcapsular Trichostatin A research buy renal space, the human fetal thymus grows significantly, is populated with a normal distribution of human thymocyte subsets and allows high levels of human T cells to repopulate the peripheral lymphoid tissues [21-23]. The BLT model is based on the severe compromised immunodeficient-humanized

(SCID-hu) mouse described by McCune and colleagues [6]. The original SCID-hu model was created using CB17-scid mice and involved the transplant of human fetal thymic tissues in the renal subcapsular space and i.v. injection of autologous or allogeneic HSC derived from the fetal liver. The SCID-hu mouse enabled the development of human T cells, which required both the implant of thymic tissues and injection of HSC. However, in CB17-scid mice the 4��8C persistence of human T cells in the peripheral

tissues was transient, as CD3+ cells were not detectable in the peripheral blood at 12 weeks post-implant and the ability of these cells to mediate an immune response was limited [64]. The persistence and functionality of human T cells was improved significantly by the use of NOD-scid mice as recipients of human thymic and liver tissues [22, 23]. However, engraftment of fetal thymic and liver tissues into NSG mice enhances human cell chimerism significantly, including reconstitution of a mucosal immune system, compared to other mouse strains [17, 65]. Continued improvement of the NSG mouse by the transgenic expression of human-specific cytokines and growth factors and expression of HLA that will allow matching with the donor tissues will further augment the development of human immune systems in BLT mice [3, 66]. In an effort to provide an analysis of optimal parameters for establishing the NSG–BLT model, we have assessed the requirement for irradiation to attain high-level human cell chimerism, the optimal implantation sites for thymic tissues, the stability of human cell chimerism and the longevity of engrafted mice.

Overall, the DNA vaccine pVAX1–TgCyP induced a significantly higher level of humoral response and splenocyte click here proliferation in BALB/c mice. A higher survival rate was attained in the pVAX1–TgCyP vaccinated group compared with the control groups. From these results, we believe that TgCyP can be an alternative vaccine

antigen for preventing T. gondii infection. In recent years, vaccine studies have predominated in the quest to prevent toxoplasmosis. Specific immune responses and efficient production have been induced in mice by DNA vaccines that have been constructed with different T. gondii antigens, including SAG1, AMA1, IMP1, ADF and MIC3 [10-13]. Cyclophilins are known to be molecular chaperones, suggesting that TgCyP and certain parasite peptides or other molecules may together engage the chemokine receptor CCR5 and a TLR molecule to trigger high production of IL-12 [17, 23-25]. Recombinant TgCyP has also been shown to have potent PPIase and IL-12-inducing activities,

thus promoting the stabilization of the T. gondii life cycle and preventing T. gondii from overwhelming its intermediate learn more hosts [17]. Furthermore, NcCyP has been shown to enhance IL-12 and IFN-γ production in dendritic cells [18]. IFN-γ, which produced by T cells and NK cells, is up-regulated by IL-12, and it is one of the most critical cytokines that mediates host protection against infection by T. gondii. In this study, the parasite antigen TgCyP was investigated as an initiation immunoregulatory molecule and was expected to trigger an antigen-specific

immune response to T. gondii by inducing IL-12 and IFN-γ. A TgCyP-specific antibody was detected in mice immunized with pVAX1–TgCyP. The survival rate after challenge with tachyzoites increased, suggesting that there is a correlation between a high anti-TgCyP antibody level and protection. Splenocytes consist of a variety of cell populations, such as B cells, T cells, dendritic cells and macrophages, all of which Olopatadine take part in several immune responses to intracellular parasite infection. Due to the high similarity between TgCyP and NcCyP, the high splenocyte proliferation in the pVAX1–TgCyP-vaccinated mice suggest that TgCyP could increase the proliferation of dendritic cells and antigen-specific CD4+ T cells, which has been previously verified for NcCyP antigen[19]. To further characterize the polarization of the immune response, we evaluated IL-2, IL-4, IL-10 and IFN-γ as indications of the Th1 and Th2 responses. IL-2 is produced primarily by T cells that express the surface antigen CD4 following allogenic activation. IL-2 is also a growth factor for all subpopulations of T-lymphocytes. T. gondii is a protozoan that is susceptible to the T-cell immunosuppressive agent cyclosporin A (CsA), and the activity of TgCyP and IL-2 synthesis in vitro has been shown to be suppressed by CsA [16].

The prevalence of ZnT8Ab varied between 58% [11] and 83% [7] in newly diagnosed T1D patients with a

general lower prevalence in the Chinese population (24%) [12]. Consistently, ZnT8R autoantibodies (ZnT8RAb) (50–54%) appear to be more frequent than ZnT8W autoantibodies (ZnT8WAb) (41–50%) [13-15] and ZnT8Q autoantibodies (ZnT8QAb) (32–36%) [14, 15] in White people. Although ZnT8QAb are found in combination with ZnT8RAb or ZnT8WAb, it selleck is rare to find patients who have only ZnT8QAb and no other islet autoantibody [16]. Importantly, ZnT8Ab have been found to react differently to the ZnT8 cytoplasmic fragment used for autoantibody detection dependent on the amino acid at position 325 [13]. The amino acid at position 325 in the COOH-terminal part of ZnT8 is controlled by the single nucleotide polymorphism (SNP) rs13266634 in the gene of ZnT8, SLC30A8 [17]. This genetic Erlotinib cost polymorphism causes an amino acid change in position 325 from arginine (CGG) present

in 69% compared to 31% for tryptophan (TGG) in healthy controls [18] and was not found to be associated with T1D in the genetic consortium (GM) genome-wide association scanning [19]. Despite the absence of an association with T1D, several authors have independently reported a correlation between the rs13266634 genotype and the autoantibody specificity of ZnT8RAb and ZnT8WAb [13, 20] [9, 21]. T1D patients with the C allele more often than expected had ZnT8RAb, and patients with the T allele had ZnT8WAb. As 30–44% of ZnT8Ab-positive subjects react with all three variants [13], that is, despite that subject is homozygous for R/R, there may still be autoantibodies that react with ZnT8W [15]. The character of the residue 325 in Farnesyltransferase ZnT8 was thought to represent a conformational epitope [22]. However, the epitope-specific reactivity to the ZnT8 268–369 in vitro transcription translation product is poorly investigated. The aims of the present study were therefore to 1) determine the immunogenicity of 15-mer short ZnT8 (318–331) peptides in mice with either R or W at position 325; 2) test the

ability of these short ZnT8 peptides to compete with radiolabelled (ZnT8 268–369) long proteins in binding to patient sera specific for either ZnT8RAb or ZnT8WAb; and 3) test the ability of the unlabelled long ZnT8 (268–369) proteins to compete with radiolabelled long ZnT8 (268–369) proteins in binding to patient sera specific for either ZnT8RAb or ZnT8WAb. Fifteen-mer peptides (short) of ZnT8R, ZnT8W and ZnT8Q (aa 318–331) covering sequences NH2-CHVATAASRDSQVVR-COOH) with R, W or Q, respectively, in the aa position 325 (Fig. 1) were synthesized by a standard Solid-phase peptide synthesis (SPPS) with 9-fluorenylmethyloxycarbonyl group (Fmoc) and determined by mass-spectrometry (MS) at Innovagen AB, Lund, Sweden. AB.

An important mucosal pathogen, and the most common cause of lower respiratory tract infections in children is respiratory syncytial virus (RSV). RSV is a negative-sense, single-stranded RNA virus of the family Paramyxoviridae. RSV enters the human body through the mucosa of the nasopharynx, where it infects epithelial cells in the presence of colonizing bacteria. Alpelisib solubility dmso Due to infection, the integrity of the epithelium is destroyed [[2, 3]]; consequently, RSV infections may result in enhanced translocation of bacterial ligands over the epithelium. Infection with RSV induces epithelial cells to

produce chemokines to attract innate immune cells to the site of infection [[4]]. During viral infection, resident and recruited innate immune cells detect viral infections, mainly by sensing viral nucleic acids. This

induces type I IFNs [[5]], the most important innate immune response against a viral infection [[6]]. Several pattern recognition receptors (PRRs) have been described AG-014699 concentration to recognize specific components of RSV. The F-protein of RSV and RSV ssRNA are recognized by TLR4 [[7]] and TLR7 [[8]], respectively. RSV ssRNA has also been shown to be recognized by nucleotide-binding oligomerization domain-2 (NOD2) [[9]]. During infection, viral dsRNA is produced, which can be recognized by TLR3 [[10]], retinoic acid-inducible gene I (RIG-I) [[11]], and possibly also by melanoma differentiation-associated gene 5 (MDA-5), although the exact role of MDA-5 is still unclear [[12]]. The majority of RSV infections result in relatively

mild symptoms, comparable with those of a common cold. However, in some cases infection with RSV may result in a severe bronchio-litis. Previous studies have shown that the bacterial composition of the lower respiratory tract is Protirelin not distinct from the upper respiratory tract, only that there are lower amounts of biomass [[13]]. Severe bronchiolitis is the result of an exaggerated proinflammatory response by RSV infected inflammatory cells [[14, 15]]. A massive influx of neutrophils in both the upper and lower airways [[4, 15, 16]] and airway obstruction can be the result. In particular, very young children are at increased risk of developing severe disease, which often leads to hospitalization. Due to the significant health burden of these infections, much effort has been invested into characterizing the risk factors contributing to disease severity. Age (<6 months), prematurity, and the presence of siblings have all been associated with increased severity [[17, 18]], though severe disease may still develop in otherwise healthy children. Hence, the pathogenesis of severe RSV disease is still poorly defined.

2a) and in the blood (Fig. 2b) and spleen (Fig. 2c,d) at 16 weeks. Irradiation was required for T cell development

in NSG mice injected with HSC, with only very low levels of human Vismodegib ic50 CD3+ cells detected in non-irradiated mice in the absence of a thymus implant. In contrast, human T cell development was not significantly different between non-irradiated and irradiated HSC-engrafted NSG mice that were implanted with human thymic tissue. Moreover, human thymic tissues recovered from non-irradiated and irradiated NSG mice showed no structural differences by H&E (Fig. 2e,f) or human CD45 staining (Fig. 2g,h). Slightly higher numbers of human CD45+ cells were recovered from thymic tissues of irradiated NSG mice at 12 weeks compared to non-irradiated mice (Supporting information, Fig. S3a), but the proportions of CD4 and CD8 single-positive thymocytes and double-positive thymocytes were similar (Supporting information, Fig. S3b). In all groups of mice that developed detectable levels of human CD3+ T cells, CD4 T cells were present at higher levels compared to CD8 T cells (Fig. 2i,j). We also evaluated if the number of CD34+ HSC injected influenced the levels of human T cells developing in the periphery. For this, NSG mice that were either non-irradiated or irradiated and then implanted with human fetal thymic and liver

tissues and HSC were evaluated for human CD3+ T cells in the peripheral blood at 12 weeks (Supporting information, Fig. S1b,d). As seen with human CD45+ levels, there was no correlation between the number of HSC-injected and levels of MAPK Inhibitor Library order human T cells in peripheral blood. To determine if irradiation influences the activation status of human T cells developing Progesterone in HSC-engrafted mice, the expression of CD45RA was examined on human CD4+ and CD8+ cells in the blood at 12 and 16 weeks and in

the spleen at 16 weeks (Supporting information, Fig. S4). CD45RA expression levels are not shown for mice injected with human HSC in the absence of irradiation due to the extremely low levels of T cell development. For NSG mice implanted with human thymic tissues and injected with HSC, irradiation did not change the CD45RA expression levels significantly on human CD4 and CD8 T cells in the peripheral blood (Supporting information, Fig. S4a,b,d,e) and spleen (Supporting information, Fig. S4c,f) compared to mice that did not receive irradiation. Interestingly, T cells from NSG mice that were irradiated and injected with HSC only were consistently lower in the expression of CD45RA compared to mice also implanted with thymic tissues, consistent with a recently published study [21], suggesting that the development of human T cells on human thymic tissue helps to maintain a naive phenotype of human T cells. Representative flow plots displaying CD45RA and CD62L staining of human CD4 (Supporting information, Fig. S4g,h) and CD8 (Supporting information, Fig.