DC Phenotype Research Articles

Development of antigen-loaded, immunosuppressive microparticles to modify dendritic cell behavior for the prevention of type 1 diabetes in NOD mice. (107.9)

Abstract Antigen-specific immunomodulation remains an important goal in the treatment of type 1 diabetes (T1D). We hypothesize that in vivo targeting of biodegradable microparticles (MPs) to DCs delivering immunomodulatory agents can promote a tolerogenic DC phenotype and induce Tregs in vivo, in order to ameliorate type 1 diabetes in NOD mice. To test this hypothesis, poly(lactide-co-glycolide) MPs were loaded with antigen - insulin B:9-23, and immunomodulatory factors - vitamin D3 (D3), TGF-B1 and GM-CSF. These MP formulations were injected subcutaneously into 4 week old female NOD mice followed by a booster at 5 weeks of age. Formulations (n = 10) consisted of a.) blank MPs, b.) MPs loaded with insulin peptide only, c.) MPs loaded with GM-CSF + insulin peptide, d.) MPs loaded with D3+TGF-B1+insulin peptide, e.) MPs loaded with GM-CSF+D3+TGF-B1 + insulin peptide. Blood glucose was measured once a week until 32 weeks of age (currently at 22 weeks). Kaplan-Meier analysis at this point reveals an overall p-value of 0.094 for survival proportions among groups, with the highest proportion of non-diabetic mice attributed to the formulation of MPs loaded with GM-CSF+D3+TGF-B1+insulin peptide (60% non-diabetic), compared to the blank MPs with the lowest proportion (20% non-diabetic), suggesting delayed onset of T1D. In vitro mechanistic assessments demonstrate MP formulations are capable of promoting tolerogenic DC phenotype and inducing syngeneic CD4+CD25+foxp3+ regulatory Tcells.

Rapamycin-induced alteration of the DC maturation process sustains their capacity to induce regulatory T cells

BackgroundDendritic cells (DC) are professional antigen-presenting cells which have unique properties to steer the outcome of immune responses. The authors previously demonstrated that repetitive injection of immature DC (iDC) was...

Maturation of Monocyte-Derived Dendritic Cells Induced by Dual Targeting of Endocytosis Receptor and CD40

AbstractAbstract 4293Dendritic cells (DC) are professional antigen presenting cells, which can induce and regulate adaptive immune responses. Hence, DC are attractive candidates for anti-tumor vaccination strategies. The aim of this study was to create recombinant bispecific Fab to target and activate DC, by using derivates of monovalent agonistic CD40 scFv and endocytosis receptors FcγRI (CD64), FcαR (CD89), DEC205 (CD205), as well as DC-SIGN (CD209), respectively. The recombinant bispecific molecules were expressed in the eukaryotic cell line Hek 293T, enriched to homogeneity by affinity chromatography and analyzed for specific binding to the targeted receptors. Functional analysis of these molecules indicated, that concurrent engagement of CD40 and endocytosis receptors expressed by immature IL-4/GM-CSF cultured monocytes-derived DC induced maturation of these DC. This was suggested by changes of DC phenotype, especially enhanced surface expression of co-stimulatory molecules like CD80 and CD86, and gain of CD83 expression as measured by flow cytometry. To particularly analyze the T cell activation properties of these DC, MACS enriched T cells of autologous donors were co-cultivated with antigen-loaded and subsequently maturated DC for seven days. After restimulation of T cells, flow cytometric detection of intracellular IFN-γ levels and surface expression of CD69 used as markers for T cell activation implies, that these DC exhibit elevated properties to activate antigen specific T cells. In contrast, a bispecific [CD64scFv × CD40scFv] Fab used as control failed to induce maturation of DC lacking CD64 expression, which may be due to abrogation of bivalent binding of this molecule and therefore CD40 cross-linking. Moreover, dual targeting with these novel immunoconstructs when linked to peptides of a tumor-associated antigen may allow direct antigen delivery to DC in combination with DC activation, and thus anti-tumor vaccination in vivo. Disclosures:No relevant conflicts of interest to declare.

Curcumin induces maturation-arrested dendritic cells that expand regulatory T cellsin vitroandin vivo

Dendritic cells (DC) and regulatory T cells (T(regs) ) are vital to the development of transplant tolerance. Curcumin is a novel biological agent extracted from Curcuma longa (turmeric), with anti-inflammatory and anti-oxidant activity mediated via nuclear factor (NF)-κB inhibition. We investigated the immunomodulatory effects of curcumin on human monocyte-derived and murine DC. Human monocyte-derived DC (hu-Mo-DC) were generated in the presence (CurcDC) or absence (matDC) of 25 µM curcumin, and matured using lipopolysaccharide (1 µg/ml). DC phenotype and allostimulatory capacity was assessed. CD11c(+) DC were isolated from C57BL/6 mice, pretreated with curcumin and injected into BALB/c mice, followed by evaluation of in vivo T cell populations and alloproliferative response. Curcumin induced DC differentiation towards maturation-arrest. CurcDC demonstrated minimal CD83 expression (<2%), down-regulation of CD80 and CD86 (50% and 30%, respectively) and reduction (10%) in both major histocompatibility complex (MHC) class II and CD40 expression compared to matDC. CurcDC also displayed decreased RelB and interleukin (IL)-12 mRNA and protein expression. Functionally, CurcDC allostimulatory capacity was decreased by up to 60% (P < 0·001) and intracellular interferon (IFN-γ) expression in the responding T cell population were reduced by 50% (P < 0·05). T cell hyporesponsiveness was due to generation of CD4(+) CD25(hi) CD127(lo) forkhead box P3 (FoxP3)(+) T(regs) that exerted suppressive functions on naïve syngeneic T cells, although the effect was not antigen-specific. In mice, in vivo infusion of allogeneic CurcDC promoted development of FoxP3(+) T(regs) and reduced subsequent alloproliferative capacity. Curcumin arrests maturation of DC and induces a tolerogenic phenotype that subsequently promotes functional FoxP3(+) T(regs) in vitro and in vivo.

Human CD34-Derived Myeloid Dendritic Cell Development Requires Intact Phosphatidylinositol 3-Kinase–Protein Kinase B–Mammalian Target of Rapamycin Signaling

Dendritic cells (DCs) are composed of different subsets that exhibit distinct functionality in the induction and regulation of immune responses. The myeloid DC subsets, including interstitial DCs and Langerhans cells (LCs), develop from CD34+ hematopoietic progenitors via direct DC precursors or monocytes. The molecular mechanisms regulating DC development are still largely unknown and mostly studied in mice. Phosphatidylinositol 3-kinase (PI3K) regulates multiple processes in myeloid cells. This study investigated the role of PI3K signaling in the development of human CD34-derived myeloid DCs. Pharmacologic inhibition of PI3K or one of its downstream targets mTOR reduced interstitial DC and LC numbers in vitro. Increased activity of this signaling module by introduction of constitutively active protein kinase B (PKB/c-Akt) increased the yields of human DC precursors in vitro as well as in transplanted beta2-microglobulin-/- NOD/SCID mice in vivo. Signaling inhibition during differentiation did not affect the acquisition of a DC phenotype, whereas proliferation and survival strongly depended on intact PI3K-PKB-mTOR signaling. Interestingly, however, this pathway became redundant for survival regulation upon terminal differentiation, which was associated with an altered expression of apoptosis regulating genes. Although dispensable for costimulatory molecule expression, the PI3K-PKB-mTOR signaling module was required for other important processes associated with DC function, including Ag uptake, LPS-induced cytokine secretion, CCR7 expression, and T cell stimulation. Thus, PI3K-PKB-mTOR signaling plays a crucial role in the development of functional CD34-derived myeloid DCs. These findings could be used as a strategy to manipulate DC subset distribution and function to regulate immunity.

CD8α+ DC are not the sole subset cross‐presenting cell‐associated tumor antigens from a solid tumor

One of the clear paradoxes in tumor immunology is the fact that cross-presentation of cell-associated tumor antigens to CD8(+) T cells is efficient, yet CTL generation is weak, and tumors continue to grow. We examined, for the first time whether this may be due to alterations in the phenotype or function of cross-presenting DC using a solid tumor model expressing a membrane bound neo-antigen (hemagglutinin, HA). Tumor antigen was constitutively cross-presented in the tumor-draining LN throughout tumor progression by CD11c(+) DC. Further analysis revealed that both CD8alpha(+) and CD8alpha(-) DC subsets, but not plasmacytoid DC, were effective at cross-presenting HA tumor antigen. The proportions of DC subsets in the tumor-draining LN were equivalent to those seen in the LN of naïve mice; however, a significant increase in the expression of the potential inhibitory B7 molecule, B7-DC, was noted and appeared to be restricted to the CD8alpha(-) DC subset. Therefore LN resident CD8alpha(+) DC are not the sole DC subset capable of cross-presenting cell-associated tumor antigens. Migratory tumor DC subsets with altered co-stimulatory receptor expression may contribute to induction and regulation of tumor-specific responses.

Effect of matrix metalloproteinase-2 on the ability of human dendritic cells to prime inflammatory TH2 cells via an IL-12 and OX40L dependent pathway.

10622 Background: Antigens expressed by melanoma cells (MAA) and recognized by T lymphocytes have been used in various immunization strategies to treat cancer patients. However, the therapeutic efficacy of these approaches remains limited. Because MMP-2 (matrix metalloproteinase-2) activity is critical for melanoma progression, this protein represents a unique antigen for vaccine therapy. Methods: CD4+ T cells were stimulated with overlapping MMP-2 peptides. After 12 days, MMP-2-specific responses were determined by intracellular staining of cytokines. Specific T cells from positive samples were enriched and cloned using limiting dilution. Cytokine production was assessed by ELISA, intracellular staining, or cytometric bead array method. Results: We identified 11 novel CD4 MMP-2-derived epitopes, and showed that the corresponding T cells, detected in the CD45RO+/CD62L- memory fraction, displayed an inflammatory TH2 profile, i.e. mainly secreting TNF, IL-4 and IL-13 and expressing the TH2-specific transcription factor GATA-3. In contrast, CD4+ T cells that recognize other associated MAAs were typically TH1. Interestingly, naïve T cells primed with active MMP-2 gave rise to TH2 specific cells, while naïve T cells primed with peptides generated IFNg-secreting specific cells, consistent with a TH1 profile. Accordingly, we showed that the MMP-2 enzyme inhibited IL-12p35 production and induced OX40L expression by DCs. Both events were responsible for the TH2 skewing of MMP-2-specific T cells and other MAA-specific T cells. Furthermore, MMP-2 specific TH2 cells were found in 13 tumor-infiltrating lymphocyte populations out of the 31 melanoma patients tested. Conclusions: The protease activity of MMP-2 influences DC phenotype, more precisely IL-12 production and OX40L expression, which are responsible for the observed TH2 lineage commitment of MMP-2-specific T cells and other MAA-specific T cells. These findings open the way to therapeutic strategies skewing these already frequent and diverse MMP-2-specific responses towards a more efficient anti-tumor TH1 phenotype to treat melanoma patients. No significant financial relationships to disclose.

IL-10 induces aberrant deletion of dendritic cells by natural killer cells in the context of HIV infection

Persistent levels of IL-10 play a central role in progressive immune dysfunction associated with chronic viral infections such as HIV, but the underlying mechanisms are poorly understood. Because IL-10 affects the phenotypic and functional properties of DCs, which are responsible for initiating adaptive immune responses, we investigated whether IL-10 induces changes in DC phenotype and function in the context of HIV infection. Here, we show that IL-10 treatment of immature and mature human DCs in culture induced contrasting phenotypic changes in these populations: immature DCs exhibited aberrant resistance to NK cell-mediated elimination, whereas mature DCs exhibited increased susceptibility to NKG2D-dependent NK elimination. Treatment of immature and mature DCs with HIV resulted in potent IL-10 secretion and the same phenotypic and functional changes observed in the IL-10-treated cells. Consistent with these in vitro data, LNs isolated from individuals infected with HIV exhibited aberrant accumulation of a partially "immature" DC population. Together, these data suggest that the progressive immune dysfunction observed in chronic viral infections might be caused in part by IL-10-induced reversal of DC susceptibility to NK cell-mediated elimination, resulting in the accumulation of poorly immunogenic DCs in LNs, the sites of adaptive immune response induction.

M1776 Toll-Like Receptor 4 (TLR4) is a Target of Wnt/β-Catenin Signaling in Intestinal Epithelial Cells (IEC): Implications for Sporadic Colon Cancer

whether colonic tissue-specific factors are responsible for re-educating DC into a gut-like phenotype. To address this issue we cultured human colonic biopsies from healthy controls and collected supernatants (SN) to condition human blood DC for 24 hours. RESULTS: Conditioning DC with SN generated In Vitro a human gut-like DC phenotype, characterized by a higher proportion of cells expressing the CCR9 (p=0.0017, n=11), β7 (p=0.0328, n=13) and CD103 (p=0.0354, n=10) gut-homingmarkers compared with their basal counterparts. A tolerogenic phenotype was also induced, characterized by reduced surface expression of the co-stimulatory markers CD40 (p=0.0297, n=9) and CD83 (p=0.0315, n=8), and also of TLR2 (p=0.0029, n=13) and TLR4 (p=0.0372, n=11). In addition, a regulatory intracellular DC cytokine profile was induced with reduced IL-12 and increased IL-10 production (n= 3). Furthermore, SN-conditioned DC demonstrated enhanced phagocytic properties (n=3), compared with those in basal conditions. These data demonstrate that human blood DC can be modulated to express the phenotype and function of human gut DC. Moreover, SNconditioned DC were less effective in stimulating proliferation of allogeneic T-cells, which subsequently expressed an increased gut/skin homing profile (n=3). CONCLUSION: We have demonstrated the relevance of the local tissue microenvironment in modulating DC since conditioning blood DC with colonic biopsy SN -through a mechanism in which vitamin A was revealed as essential but not sufficienthave the capacity to condition DC into gutlike DC with unique properties rendering them crucial for oral tolerance. Identifying all the molecules related to the generation of the tolerogenic gut-like DC would provide us with new targets for immunomodulation in patients suffering from IBD, where the functionality of gut-DC is altered leading to a lack of oral tolerance against the commensal microbiota.

Integration of HSP90 inhibitors in combinational immunotherapy targeting receptor tyrosine kinases (RTKs) in cancer (131.45)

Abstract Background: Receptor tyrosine kinases (RTKs) and HSP90 play important roles in tumor growth, survival and metastasis. An effective therapeutic approach would promote decreased expression of RTKs on tumor cells, while increasing presentation of RTK-derived peptides in tumor cell MHC class I complexes, thereby enhancing the efficacy of anti-RTK CD8+ T effector cells. Aim: We are assessing the safety and effectiveness of the HSP90 inhibitor 17-DMAG in enhancing anti-tumor immunotherapy with RTK-specific T cells in murine tumor models. Methods: We tested the effect of 17-DMAG on tumor cell viability, proliferation and expression of RTK and the MHC I antigen-processing machinery in vitro. We also assessed the effect of 17-DMAG on DC phenotype and function. Results: 17-DMAG facilitated a dose-dependent reduction in RTK expression, but had no adverse effects on the antigen-processing machinery of the tumors. Anti-RTK CD8+ T cells exhibited improved recognition of DMAG-treated tumor cells in vitro. However, 17-DMAG treatment of DC resulted in decreased co-stimulatory molecule expression, IL-12p70 production and allo-stimulatory capacity by these APC in vitro. Conclusion: 17-DMAG treatment promotes immunologically-preferred alterations in tumor cells, but potentially adverse effects on DC functions in vitro. In vivo studies are warranted to assess the net anti-tumor impact of combinational immunotherapies integrating 17-DMAG.

ATP and lipoteichoic acid act cooperatively to induce a DC phenotype that promotes Th17 in an IL-23- and IL-1B-dependent manner (89.28)

Abstract We investigated whether pairing TLR ligands with an “endogenous” danger signal, extracellular adenosine triphosphate (ATP), would act in synergy to induce in monocytes unique DC-like properties. The TLR2 ligand lipoteichoic acid (LTA) and ATP were efficient partners for cooperatively enhancing expression of IL-23 and IL-1b when monocytes were cultured in GM-CSF, but not when IL-4 was included. These cells showed DC-like properties including activated DC surface phenotype and enhanced migration towards CCR7 ligands. They also preferentially skewed allogenic CD4pos T lymphocyte responses toward the IL-22hi, IL-17hi/IFN-glo Th17 phenotype, a capacity inhibited by neutralization of either IL-23 or IL-1b, but not IL-6. Although pharmacological activation of either ionotropic or cAMP-dependent pathways acted in together with LTA to enhance IL-23, only inhibition of the cAMP-dependent pathway antagonized enhancement of cytokine production by ATP. In addition, ATP plus atypical lipopolysaccharide from P. gingivalis (signaling through TLR2) was superior to E. coli-derived LPS (TLR4 ligand) for promoting the high IL-23-secreting DC-like phenotype, but considerably inferior for inducing IL-12 p70 production when paired with IFN-g. Collectively, our data suggests TLR2 ligands encountered by innate immune cells in an environment rich in extracellular ATP can induce a distinct activation state that supports an IL-23- and IL-1b-dependent Th17 type response.

Interleukin-2 Controls flt3L-dependent Development and Phenotype of Conventional and Plasmacytoid Dendritic Cells (36.19)

Abstract DC development requires the ligand for FMS-like tyrosine kinase 3 receptor (flt3L), but little is known regarding other cytokines that may control this process. In our study, we have addressed the effect of IL-2 on DC development. We have shown that the addition of IL-2 to flt3L-stimulated bone marrow (BM) cultures can block the development of both pDCs (CD11c+SiglecH+) and cDCs (CD11c+CD11b+), while expanding the populations of NK/NKT/T cells (CD3+/-NK1.l+/-). By sorting for DC precursors that are Lineage- flt3+ CD11c-, we confirm that IL-2 blocks DC development by acting directly on DC precursors, and not indirectly via its effect on NK/NKT/T cells. The inhibition of DC development by IL-2 is dependent on both the IL-2R alpha and beta chains, and STAT5. IL-2 treatment of DC precursors leads to a decrease in the expression of various transcription factors crucial for DC development. In addition, our ongoing studies indicate that the presence of IL-2 during flt3L-dependent DC development also alters the phenotype of DCs. Together our data has indicated that IL-2 inhibits the development of DCs, and suggests IL-2 can also alter DC phenotype. This has important implications in the therapeutic use of IL-2, as well as our current understanding on factors that can lead to the loss of immune tolerance in various autoimmune diseases.

HLA-Identical Dendritic-Leukemic Cell Hybrids Generate Specific CTLs in Vitro

hile being instrumental in the treatment of leukemic relapse after allogeneic hematopoietic stem cell transplantation, the impact of donor lymphocyte infusion (DLI) and its effectiveness remain debatable. Consequently it is widely accepted that more efforts are needed in order to make DLI more effective. This communication thus deals with the generation of specific CTLs in the clinical setting of HLA matched hematopoietic stem cell transplantation, to be used as an improved DLI treatment for post-transplantation relapsed leukemias. We assessed the potential of fused dendritic cells from donor origin, with leukemic cells from the HLA matched recipient for the generation of donor anti-tumor CTLs. Leukemic cells and donor dendritic cells were fused using polyethylene glycol (PEG). The hybrids were analyzed for double phenotype of both DC and tumor, and used for the education and generation of cytotoxic donor lymphocytes. Results demonstrate that efficient and specific CTLs can be generated and used in vitro for the elimination of the recipient tumor cells. These results form the basis for the establishment of a novel methodology aimed at generating active or passive anti-leukemic vaccine in relapsed patients.

Dendritic cells transmit HIV-1 through human small intestinal mucosa

To dissect the early events in the transmission of HIV-1 from mother to child, we investigated whether DCs participate in HIV-1 entry into human small intestinal mucosa. We isolated human MNLs from jejunal lamina propria and identified a subpopulation of CD11c(+)HLA-DR(+) MNLs that expressed DC-SIGN, CD83, CD86, CD206, and CCR7, indicating a DC phenotype. Jejunal DCs also expressed the HIV-1 receptor CD4 and coreceptors CCR5 and CXCR4 and in suspension rapidly took up cell-free HIV-1. HIV-1 inoculated onto the apical surface of explanted jejunum was transported by lamina propria DCs through the mucosa and transmitted in trans to blood and intestinal lymphocytes. These findings indicate that in addition to intestinal epithelial cells, which we showed previously transcytose infectious HIV-1 to indicator cells, intestinal DCs play an important role in transporting HIV-1 through the intestinal mucosa and the subsequent transmission to T cells.

Antigen processing and MHC-II presentation by dermal and tumor infiltrating Dendritic Cells (78.26)

Abstract MHC-II presentation by DC is necessary for both initial CD4 T cell priming and for peripheral effector function. We have previously found that naïve tumor-specific CD4 T cells were ignorant to poorly immunogenic murine tumors, suggesting a possible insufficiency in DC function. Here, we investigated the phenotype, antigen uptake and MHC-II presentation capacity of normal dermal DC (DDC) and tumor infiltrating DC (TIDC) in lymphoid and peripheral sites. We found that tumors were extensively infiltrated by partially mature TIDC that were phenotypically similar to DDC. However, TIDC were inefficient at MHC-II presentation due to poor intrinsic protein uptake capability. This resulted in both inferior initiation of T cell responses in the draining LN and poor peripheral effector cell accumulation. In addition, toll-like receptor stimulation selectively enhanced MHC-II antigen presentation by DDC but not TIDC in the draining LN, and did not affect overall peripheral antigen uptake of either. These results show that TIDC are functionally distinct from normal interstitial DC, indicating that neoplastic tissues can evade effector CD4 T cells through modification of DC competence. NIH AI34824(M.F.M.), CA82596(M.F.M.), NCI 2 T32(M.Y.G.).

Early viraemia clearance during antiviral therapy of chronic hepatitis C improves dendritic cell functions

Plasma and cellular HCV RNA and core antigen were tested in monocyte-derived DC (MDDC) from chronic hepatitis C patients undergoing treatment with peg-interferon alpha2b/ribavirin. DC allostimulatory capacity, HCV-specific T-cell reactivity and IL-12 production were measured at baseline and treatment week (TW)12. Using DC and autologous CD4(+)T-cells, obtained at baseline and TW12, we performed cross-over experiments to determine the relative role of DC and/or T-cells for impaired immune reactivity to HCV. HCV RNA and HCV core plasma levels had an impact on DC phenotype and allostimulatory capacity. In contrast, HCV genome/core protein, although detectable in DC from some patients had no effect on DC function. Antiviral immunity at TW12 was not improved in patients who remained HCV RNA positive, while early viraemia clearance (TW12) improved antiviral responses. The cross-over experiment revealed that changes in DC, rather than CD4(+)T cells have a major role for enhanced anti-HCV responses.

Imprinted DC mediate the immune‐educating effect of early‐life microbial exposure

It has been long proposed that exposure to environmental factors early in life may have an educating effect on the development of immune regulatory functions. However, experimental studies on this issue are limited and the related molecular and cellular basis remains unclear. Here we report that neonatal exposure to killed bacteria (Chlamydia muridarum, originally called Chlamydia trachomatis mouse pneumonitis (MoPn)) changed the pattern of the hosts' immune responses to a model allergen (OVA) in adulthood. This was associated with altered phenotype and function of DC. We found that DC from adult mice treated neonatally with UV-killed MoPn exhibited distinct patterns of surface marker and TLR expression and cytokine production from control mice (DC from adult mice neonatally treated with vehicle, (Sham-DC)). More importantly, DC from adult mice treated neonatally with UV-killed MoPn induced significantly lower type-2 antigen-specific T-cell responses than Sham-DC shown in DC:T co-culture experiments in vitro and in adoptive transfer experiments in vivo. In addition, depletion of T cells in vivo largely abolished the phenotypic and functional alterations of DC caused by bacterial exposure, suggesting the involvement of T cell in this process. Our study demonstrates a central role of DC in linking the early-life exposure to microbial products and the balanced development of immune regulatory functions and the involvement of T cells in imprinting of the DC function.

Phenotype and function of neonatal DC

Newborns face complex physical and immunological changes before and after birth. Although the uterus is a sterile environment for the fetus, it also contains non-self material from the mother. Birth involves the transition from the sterile intra-uterine environment to an environment rich in microbes and requires rapid induction of appropriate responses to control these microbes. In this review we focus on the similarities and differences of human and murine neonatal DC and their reaction to various stimuli. A better understanding of the newborn immune system--in particular, the DC-T-cell interaction--will be beneficial for the development of improved strategies to prevent or treat infections in this vulnerable population and prepare the immune system to cope with allergens and tumors later in life.

OR.53. Synergistic Modulation of Human DC Phenotype and Function by Vitamin D Analogue and Histone Deacetylase Inhibitor

OR.53. Synergistic Modulation of Human DC Phenotype and Function by Vitamin D Analogue and Histone Deacetylase Inhibitor

T.31. Antigen Dose Over-rides DC Phenotype in the Control of CD4 + Regulatory T Cell Induction

T.31. Antigen Dose Over-rides DC Phenotype in the Control of CD4 + Regulatory T Cell Induction