Functional modulation of CD8+ T cell by approved novel immune enhancer: Nocardia rubra Cell-Wall Skeletons (Nr-CWS)

Nocardia rubra cell wall skeleton (Nr-CWS) has been reported to have innate immunostimulating and anti-tumor activities. However, the immunomodulatory effects of Nr-CWS on CD8+ T cells and their related mechanisms are still unknown. In this work, our team purified CD8⁺T cells from spleen cells and explored the phenotype and function of NR-CWS in vitro on CD8⁺T cells. We observed that Nr-CWS can significantly up-regulate the expression of CD69 and CD25 on CD8⁺T cells, with no significant effect on apoptosis or cell death of CD8⁺T cells that occurs in vitro during culture. In addition, the effect of perforin and granzyme B was increased after Nr-CWS treatment, but did not substantially alter the expression of TRAIL and FasL. A variety of cytokine analyses have shown that of the cytokines examined (IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-6 and IL-10), only IFN-γ and TNF The increase in -α was more pronounced, and the effect of Nr-CWS in CD8⁺T cell culture medium on CD8+ T cells was independent of Th cells. Our results demonstrated that Nr-CWS could up-regulate CD69 and CD25 expression on CD8⁺T cells, promoting IFN-γ and TNF-α secretion, and enhancing perforin and granzyme B production. Thus Nr-CWS may have Immunoaugmenting therapeutic activity via an increase in CD8⁺T cells response.     

Thymol as a reciprocal regulator of T cell differentiation: Promotion of regulatory T cells and suppression of Th1/Th17 cells

Regulatory T cells (Tregs) are critical for maintaining immune response and enhancing their differentiation has therapeutic implications for autoimmune diseases. In this study, we investigated the effects of thymol a well-known monoterpene from Thyme on differentiation and function of Tregs. In vitro generation of Tregs from purified naïve CD4⁺CD25⁻ T cells in the presence of thymol was carried out. Suppressor activity of generated Tregs was examined by changes in the proliferation of CFSE-labeled conventional T cells. Thymol promotes differentiation of naïve CD4⁺CD25⁻ T cells to CD4⁺CD25⁺Foxp3⁺ Tregs [66.9–71.8% vs. control (47%)] and increased intensity of Foxp3 expression on Tregs (p < 0.01). In functional assay, an increased immune suppression by thymol-induced Tregs (≈2.5 times of untreated Tregs) was detected. For in vivo study, thymol was intraperitoneally administered to ovalbumin (Ova)-immunized mice. Flow cytometry assessment of spleens from thymol-treated Ova-immunized mice showed increased number of CD4⁺ Foxp3⁺ Tregs (>8%, p < 0.01(and decreased levels of CD4⁺T-bet⁺ Th1 and CD4⁺RORγt⁺ Th17 cells resulted in significant decreased Th1/Treg and Th17/Treg ratios. In ex vivo Ova challenge of splenocytes from thymol-treated Ova-immunized mice, similarly higher levels of CD4⁺ Foxp3⁺ Tregs, and also elevated TGF-β expression in CD4⁺Foxp3⁺ population (48.1% vs. 18.9% in untreated Ova-immunized group) and reduced IFN-γ-producing CD4⁺T-bet⁺ T cells and IL-17-producing CD4⁺RORγt⁺ T cells were detected. This led to marked decreased ratios of IFNγ/TGF-β and IL-17/TGF-β expressions. In conclusion, this study revealed thymol as a compound with enhancing effects on Treg differentiation and function, which may have potential benefits in treatment of immune-mediated diseases with Th1/Th17 over-activation.     

Decreased severity of experimental autoimmune encephalomyelitis during resveratrol administration is associated with increased IL-17+IL-10+ T cells,CD4− IFN-γ+ cells,and decreased macrophage IL-6 expression

Experimental autoimmune encephalomyelitis (EAE), an animal model of Multiple Sclerosis, is induced after injection of PLP_139–151 myelin peptide in complete Freund's adjuvant into SJL/J mice. During EAE, T cells and macrophages infiltrate the brain, produce cytokines IL-17, IFN-γ, TNF-α, or IL-6, and bring about autoimmune neuroinflammation. However, infiltrating T cells which simultaneously produce IL-17 and IL-10 or infiltrating CD4⁻ NKT cells that produce IFN-γ protect against EAE. Resveratrol, a plant polyphenol, exhibits anti-inflammatory properties. To determine if resveratrol can relieve EAE, SJL/J mice were administered diets enriched in resveratrol at EAE injection. EAE symptoms were significantly less compared with controls in mice fed resveratrol. At day 56 of EAE, splenic T cells from mice fed 0%, 0.04% or 0.08% resveratrol that were restimulated with PLP_139–151 produced similar levels while splenic T cells from mice fed 0.02% resveratrol produced significantly higher levels of IL-17, IFN-γ, and TNF-α. At peak EAE (day 14), mice fed resveratrol had higher numbers of IL-17⁺ T cells, IL-17⁺/IL-10⁺ T cells, and CD4⁻IFN-γ ⁺ cells in the brain and spleen compared with controls. Adoptive transfer of day 14 EAE encephalogenic T cells into mice fed resveratrol reduced the severity of EAE. In addition, resveratrol directly suppressed expression of IL-6 and IL-12/23 p40 but increased expression of IL-12 p35 and IL-23 p19 from macrophages. Therefore resveratrol protection against EAE is not associated with declines in IL-17⁺ T cells but is associated with rises in IL-17⁺/IL-10⁺ T cells and CD4^-IFN-γ⁺ and with repressed macrophage IL-6 and IL-12/23 p40 expression.     

Th9 cells promote antitumor immunity via IL-9 and IL-21 and demonstrate atypical cytokine expression in breast cancer

Breast cancer is a major cause of cancer-related death in women. Antitumor T cell responses play critical therapeutic roles, including direct cytotoxicity mediated by CD8⁺ T cells and immunomodulatory roles mediated by CD4⁺ T cells. The IL-9-expressing Th9 cells are recently found to present antitumor immunity in melanoma and lung adenocarcinoma. In this study, we found that IL-9 expression in the serum and in circulating CD4⁺ T cells were significantly upregulated in breast cancer patients compared to healthy controls. The IL-9-expressing Th9 cells were enriched in the CCR4⁻ CCR6⁻ CXCR3⁻ subset. Upon TCR stimulation, this subset also presented potent IL-10 and IL-21 expression in addition to IL-9 expression. CCR4⁻ CCR6⁻ CXCR3⁻ CD4⁺ T cells also assisted in the killing of autologous tumor cells by CD8⁺ T cells, but did not initiate cytotoxicity by themselves. This enhancement in CD8⁺ T cell-mediated cytotoxicity was dependent on IL-9 as well as on IL-21. Interestingly, the tumor-infiltrating Th9 cells presented comparable IL-9, reduced IL-10, and elevated IL-21 expression compared with their counterparts in the peripheral blood. Together, these results demonstrated that IL-9-expressing Th9 cells were upregulated in breast cancer patients and potentially possessed antitumor roles by enhancing CD8⁺ T cell-mediated cytotoxicity.     

HIV infection confers distinct mechanisms in severe drug eruption: Endogenous virus activation with aberrant Th2/Th1 and CD8+ T cells function

Severe drug eruption (SDE), a common skin disease, becomes dangerous when it occurs in patients with human immunodeficiency virus (HIV). However, the molecular mechanisms are poorly understood. Forty patients including HIV⁺ SDE⁺ (n = 15), HIV⁻ SDE⁺ (n = 15) and HIV⁺ SDE⁻ (n = 10) subjects were enrolled in our study. All HIV⁺ patients were at acquired immune deficiency syndrome (AIDS) stage. Serum levels of TNF-α, IFN-γ, IL-4, IL-13, IL-6, CXCL9, and CCL17 were quantified by ELISA. Epstein–Barr virus (EBV) and cytomegalovirus (CMV) loads were quantified by RT-qPCR. CD4, CD8, Th1, Th2, TNF-α-CD8, and IFN-γ-CD8 T cell populations were measured by flow cytometry. Levels of biochemical indexes in HIV⁺ SDE⁺ patients were significantly different from in HIV⁻ SDE⁺ patients (P < .05). EBV and CMV viral loads were significantly higher in HIV⁺ SDE⁺ patients, but not in HIV⁻ SDE⁺ patients (P < .05). Inflammatory cytokines TNF-α and IFN-γ were significantly elevated in HIV⁺ SDE⁺ patients (P < .05). Th2/Th1 populations and TNF-α secreting or IFN-γ secreting CD8⁺ T cells, were significantly up-regulated in HIV⁺ SDE⁺ patients compared to HIV⁻ SDE⁺ patients (P < .05). Conversely, the CD4/CD8 ratio was significantly down-regulated in HIV⁺ SDE⁺ patients compared to HIV⁻ SDE⁺ patients (P < .05). HIV infection confers distinct clinical phenotypes and immune inflammatory mechanisms in SDE. Sustained EBV and CMV activation, unbalanced Th2/Th1 and overactive CD8⁺ T cells mediating a pro-inflammatory response could act as distinct mechanisms in the aggravation of SDE in HIV⁺ SDE⁺ patients.     

Direct effects of interleukin-8 on growth and functional activity of T lymphocytes

CD3⁺ T-lymphocytes were isolated from the normal donors by positive magnetic separation. Activation of the T cells with particles conjugated with antibodies to CD3, СD28 and СD2 molecules led to a marked increase in T-cell production of interleukine-8 (IL-8). We present evidence that IL-8 receptor α-chain (CXCR1, CD181) is expressed on the cell surface of 13.3% T cells. Activation of T-lymphocytes resulted in significant enhancement of CD181⁺ cells both in naive CD4⁺ T cell and terminally differentiated effector CD4⁺ T cell compartments with concomitant reduction of CD181⁺ cells in effector memory CD4⁺ T cell subset. The level of T cell activation was assessed judging from the surface expression of CD25 (IL-2 receptor α-chain). We demonstrate that IL-8 treatment (0.01–10.0 ng/ml concentration range) reduced the activation status of both CD4⁻ and CD4⁺ effector memory T cells, as well as terminally differentiated effector T cells, without significantly affecting the activation of naive T cells or central memory T cells. In addition, IL-8 up-regulated IL-2 and down-regulated IL-10 production by activated T cells, with no effect on interferon-gamma (IFN-γ) and IL-4 production. Data obtained suggests the importance of IL-8 in the direct regulation of adaptive T cell reactivity.     

CXCR5+ CD8+ T cells present elevated capacity in mediating cytotoxicity toward autologous tumor cells through interleukin 10 in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a common and aggressive subtype of non-Hodgkin's lymphomas, with limited treatment options in refractory and relapsed patients. Growing evidence supports the notion that CD8⁺ T cell immunity could be utilized to eliminate B cell lymphomas. CXCR5⁺ CD8⁺ T cell is a novel cell subtype and share CXCR5 expression with CD19⁺ tumor cells. In this study, we investigated the frequency and function of existing CXCR5⁺ CD8⁺ T cells in DLBCL patients. We found that DLBCL patients as a group demonstrated significantly higher level of CXCR5⁺ CD8⁺ T cells than healthy individuals, with huge variability in each patient. Using anti-CD3/CD28-stimulated CD8⁺ T cells as effector (E) cells and autologous CD19⁺ tumor cells as target (T) cells, at high E:T ratio, no difference between the intensities of CXCR5⁺ CD8⁺ T cell- and CXCR5⁻ CD8⁺ T cell-mediated cytotoxicity were observed. However, at intermediate and low E:T ratios, the CXCR5⁺ CD8⁺ T cells presented stronger cytotoxicity than CXCR5⁻ CD8⁺ T cells. The expressions of granzyme A, granzyme B, and perforin were significantly higher in CXCR5⁺ CD8⁺ T cells than in CXCR5⁻ CD8⁺ T cells, with no significant difference in the level of degranulation. Tumor cells in DLBCL were known to secrete high level of interleukin 10 (IL-10). We therefore blocked the IL-10/IL-10R pathway, and found that the expressions of granzyme A, granzyme B, and perforin by CXCR5⁺ CD8⁺ T cells were significantly elevated. Together, these results suggest that CXCR5⁺ CD8⁺ T cells are potential candidates of CD8⁺ T cell-based immunotherapies, could mediate elimination of autologous tumor cells in DLBCL patients, but are also susceptible to IL-10-mediated suppression.     

The source of Mycobacterium tuberculosis-specific IFN-γ production in peripheral blood mononuclear cells of TB patients

Mycobacterium tuberculosis (Mtb)-specific IFN-γ secretion plays important roles in anti-tuberculosis (TB) immunity. Mtb-specific IFN-γ response can be induced in HIV/TB co-infected patients with a low CD4 lymphocyte count; this suggests that the source of Mtb-specific IFN-γ production is not limited in CD4⁺ T lymphocytes. Currently, the major sources of Mtb-specific IFN-γ production and the function and phenotype of Mtb-specific IFN-γ-producing cells still remain unclear. Thirty-nine participants (24 active TB patients, 10 HIV/TB co-infected patients, and 5 healthy volunteers) were recruited according to conventional tests and Mtb-specific IFN-γ ELISPOT assay. Multicolor flow cytometry was used to investigate the production of intracellular IFN-γ in peripheral blood mononuclear cells (PBMCs) after Mtb-specific antigen stimulation. Our results showed that CD4⁺, CD8⁺ T cells and NK cells are all major sources of Mtb-specific IFN-γ production in PBMCs of TB patients. Moreover, CD8⁺ T cells are the highest number of Mtb-specific IFN-γ-producing cells in HIV/TB co-infected patients. Although the activity of NK cells is significantly reduced in TB patients when compared with healthy controls, Mtb-specific antigen stimulation induces a significant increase in NK cell activity. We also showed that CD45RO is the characteristic marker of Mtb-specific IFN-γ-producing T cells but not that of Mtb-specific IFN-γ-producing NK cells in peripheral blood. High expression of CD11a may be the characteristic feature of Mtb-specific IFN-γ-producing NK cells. This study put forward a new insight on the source of antigen-specific IFN-γ-production in PBMCs of TB patients.     

CD4+ B220+ TCRγδ+ T cells produce IL-17 in lupus-prone MRL/lpr mice

Systemic lupus erythematosus is an autoimmune disease with comprehensive immune cell disorders. Recent studies suggested that pro-inflammatory cytokine IL-17 plays important role in lupus, leaving the cellular sources and their pathogenic and physiologic characters largely unknown. In the current study, by using lupus-prone MRL/lpr mice, we demonstrated that Th17 response prevails in lupus disease regarding significantly accumulated serum IL-17, increased IL-17-producing splenocytes, and elevated phospho-STAT3 in CD4⁺ T cells. Intracellular staining revealed that unusual CD4⁺ B220⁺ T cells are major IL-17-producing cells, whereas conventional CD4⁺ B220⁻ T cells are major IFN-γ-producing cells. Subsequent studies showed that CD4⁺ B220⁺ cells contains both αβ and γδ T cells in the spleen and thymus of MRL/lpr mice. Further study showed that around 60% of γδ T cells in MRL/lpr mice co-express both B220 and CD4 on their surface, and are the major RORγt⁺ cells in MRL/lpr mice. Finally, CD4⁺ B220⁺ T cells alone do not proliferate, but could enhance the proliferation and IFN-γ-production of conventional CD4⁺ B220⁻ T cells. Our findings suggest the pathogenic role of unusual CD4⁺ B220⁺ T cells in lupus disease in MRL/lpr mice according to their IL-17-producing ability and stimulatory function for conventional CD4⁺ B220⁻ T cells.     

Alloantigen specific T regulatory cells in transplant tolerance

CD4⁺CD25⁺Foxp3⁺T cells are regulatory/suppressor cells (Treg) that include non-antigen(Ag)-specific as well as Ag-specific Tregs. How non-Ag-specific naïve CD4⁺CD25⁺Treg develop into specific Tregs is unknown. We have studied DA rats tolerant to fully allogeneic PVG cardiac grafts that survived with out immunosuppression for over 100 days and identified the cellular basis of alloantigen specific tolerance. Key observations from our studies will be reviewed including how CD4⁺CD25⁺Tregs were first identified and the cytokine dependence of CD4⁺T cells that transfer alloantigen specific transplant tolerance which died in culture unless stimulated with both cytokine rich ConA supernatant and specific donor alloantigen. Both the tolerant CD4⁺CD25⁺ and CD4⁺CD25⁻ T cell populations are required to transfer tolerance, yet alone the CD4⁺CD25⁻ T cell effect rejection. Tolerance transfer occurs with a low ratio of CD4⁺CD25⁺T cells (< 1:10), whereas to induce tolerance with naive CD4⁺CD25⁺T cells requires both a ratio of > 1:1 and is not alloantigen specific.Recent findings on how naïve CD4⁺CD25⁺T cells developed into two separated pathways of alloantigen specific Tregs, by culturing them with alloAg with either IL-2 or IL-4 and donor alloantigen are described. IL-2 enhances IFN-γR and IL-5 mRNA while IL-4 induced a reciprocal profile with de novo IL-5Rα and increased IFN-γ mRNA expression. Both IL-2 and IL-4 alloactivated CD4⁺CD25⁺Tregs within 3–4 days of culture can induce alloantigen specific tolerance at ratios of 1:10. Long term, CD4⁺CD25⁺T cells from tolerant hosts given IL-2 cultured cells have increased IL-5 and IFN-γR mRNA; whereas hosts given IL-4 cultured cells had enhanced IL-5Rα mRNA expression and IL-5 enhanced their proliferation to donor but not third party alloAg.These findings suggest that Th1 and Th2 responses activate two pathways of alloantigen specific Tregs that can mediate transplant tolerance but are dependent upon cytokines produced by ongoing Th1 and/or Th2 immune responses.     

Omega-3 fatty acid-derived mediator,Resolvin E1, ameliorates 2,4-dinitrofluorobenzene-induced atopic dermatitis in NC/Nga mice

Atopic dermatitis (AD) is a common inflammatory skin disease for which few effective treatments are available. Resolvin E1 (RvE1; 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid) is an endogenous lipid mediator derived from omega-3 fatty eicosapentaenoic acid, which is a potent inhibitor of inflammation. AD-like skin lesion was induced by repetitive skin contact with DNFB in NC/Nga mice and the effects of RvE1 were evaluated on the basis of histopathological findings of skin, ear swelling and cytokine production of CD4⁺ T cells. Intraperitoneal injection of RvE1 for one week after DNFB challenge significantly lowered ear swelling and improved back skin lesions. In addition, RvE1 significantly suppressed production of interferon-gamma (IFN-γ) and interleukin-4 (IL-4) by activated CD4⁺ T cells and serum IgE level. Furthermore, RvE1 reduced DNFB-induced infiltration of eosinophils, mast cells, CD4⁺ T cells, and CD8⁺ T cells in skin lesions.Therefore, RvE1 may suppress the development of AD-like skin lesions in DNFB-treated NC/Nga mice by reducing IL-4 and IFN-γ of activated CD4⁺ T cells and serum IgE levels and infiltration of immune cells to skin lesion.     

Paeoniflorin inhibits the maturation and immunostimulatory function of allergen-induced murine dendritic cells

Dendritic cells (DCs) as the front lines of defense play a crucial role in allergic contact dermatitis (ACD). Paeoniflorin (PF) has been clinically proven to be effective in the treatment of inflammatory skin diseases such as ACD. However, the mechanisms underlying the anti-inflammatory effect of PF remain unclear. The aim of this study was to explore the effect of PF on the maturation and immunostimulatory function of DCs in the murine model of ACD in vitro. Murine bone marrow-derived DCs were stimulated with the contact sensitizer 1-chloro-2, 4-dinitrobenze (DNCB) in vitro. Surface antigen expression of DCs (MHC II, CD40, CD80, and CD86), as an indicator of maturation DCs and cytokines (IL-12, IFN-γ, IL-10, and TGF-β) after DNCB stimulation in the absence or presence of PF at different doses, was detected. Then, we detected that PF-treated DCs stimulated T cells in response to DNCB. PF inhibited the up-regulation of MHC II, CD80, CD86, and CD40, decreased IL-12p70 secretion, while increased the production of IL-10 and TGF-β, and had no effect on IFN-γ cytokine production by murine bone marrow-derived DCs in response to DNCB. DCs exposed to PF had diminished capacity to stimulate allogeneic T cell proliferation and to activate IFN-γ-producing CD4⁺ T cells and induced CD4⁺CD25⁺Foxp3⁺ T cells and IL-10-producing T cell expansion from naïve CD4⁺ T cells. These results indicate that PF may be effective in preventing and treating ACD in vitro and other inflammatory responses possibly through inhibiting maturation of DCs and limiting their capacity to stimulate T cell responses.     

Circulating follicular helper T cells presented distinctively different responses toward bacterial antigens in primary biliary cholangitis

Primary biliary cholangitis (PBC) is a chronic and progressive cholestatic liver disease with unknown causes. The initiation of PBC is associated with bacterial infections and abnormal immune correlates, such as the presence of self-reactive anti-mitochondrial antibodies and shifted balance of T cell subsets. In particular, the CD4⁺ CXCR5⁺ follicular helper T (Tfh) cells are highly activated in PBC patients and are significantly associated with PBC severity, but the underlying reasons are unknown. In this study, we found that the circulating CD4⁺ CXCR5⁺ T cells were enriched with the interferon (IFN)-γ-secreting Th1-subtype and the interleukin (IL)-17-secreting Th17-subtype, but not the IL-4-secreting Th2 subtype. We further demonstrated that a host of microbial motifs, including Pam3CSK4, poly(I:C), LPS, imiquimod, and CpG, could significantly stimulate IFN-γ, IL-17, and/or IL-21 from circulating CD4⁺ CXCR5⁺ T cells in PBC patients, especially in the presence of monocytes and B cells. Whole bacterial cells of Escherichia coli, Novosphingobium aromaticivorans, and Mycobacterium gordonae, could also potently stimulate IFN-γ, IL-17, and/or IL-21 production from circulating CD4⁺ CXCR5⁺ T cells. But interestingly, while the whole cell could potently stimulate circulating CD4⁺ CXCR5⁺ T cells from both healthy controls and PBC patients, the cell protein lysate could only potently stimulate circulating CD4⁺ CXCR5⁺ T cells from PBC patients, but not those from healthy controls, suggesting that circulating CD4⁺ CXCR5⁺ T cells in PBC patients had distinctive antigen-specificity from those in healthy individuals. Together, these data demonstrated that bacterial antigen stimulation is a potential source of aberrant Tfh cell activation in PBC patients.     

Compact bone-derived mesenchymal stem cells attenuate nonalcoholic steatohepatitis in a mouse model by modulation of CD4 cells differentiation

Increasing evidence has accrued which indicates that mesenchymal stem cells (MSCs) have a potential clinical value in the treatment of certain diseases. Globally, nonalcoholic steatohepatitis (NASH) is a widespread disorder. In the present study, MSCs were isolated successfully from compact bone and a mouse model of NASH was established as achieved with use of a methionine-choline deficient (MCD) diet. Compact bone-derived MSCs transplantation reduced MCD diet-induced weight loss, hepatic lipid peroxidation, steatosis, ballooning, lobular inflammation and fibrogenesis. It was shown that MSCs treatment hampered MCD diet-induced proliferation of CD4⁺ IFN-γ⁺ and CD4⁺ IL-6⁺ T spleen cells. In addition, CD4⁺ IL-17⁺ lymphocytes that associated with anti-inflammation show little change in MCD as well as in MCD + MSCs splenocytes. We conclude that MSCs may have a potential clinical value upon NASH, through their capacity to suppress activation of CD4⁺ IFN-γ⁺ and CD4⁺ IL-6⁺ lymphocytes.     

Ferritin protein cage nanoparticles as versatile antigen delivery nanoplatforms for dendritic cell (DC)-based vaccine development

We utilized ferritin protein cage nanoparticles (FPCN) as antigen delivery nanoplatforms for DC-based vaccine development and investigated DC-mediated antigen-specific immune responses. Antigenic peptides, OT-1 (SIINFEKL) or OT-2 (ISQAVHAAHAEINEAGR) which are derived from ovalbumin, were genetically introduced either onto the exterior surface or into the interior cavity of FPCN. FPCN carrying antigenic peptides (OT-1-FPCN and OT-2-FPCN) were effectively delivered to DCs and processed within endosomes. Delivered antigenic peptides, OT-1 or OT-2, to DCs successfully induced antigen-specific CD8⁺ or CD4⁺ T cell proliferations both in vitro and in vivo. Naïve mice immunized with OT-1-FPCN efficiently differentiated OT-1 specific CD8⁺ T cells into functional effector cytotoxic T cells resulting in selective killing of antigen-specific target cells. Effective differentiation of proliferated OT-2 specific CD4⁺ T cells into functional CD4⁺ Th1 and Th2 cells was confirmed with the productions of IFN-γ/IL-2 and IL-10/IL-13 cytokines, respectively.From the Clinical EditorIn this study, the authors utilized ferritin protein cage nanoparticles as antigen delivery nanoplatforms for dendritic cell-based vaccine development and investigated DC-mediated antigen-specific immune responses using strong model antigens derived from ovalbumin, suggesting potential future clinical applicability of this or similar techniques.