Memory Th2 Research Articles

Abstract CT021: INVAC-1, an optimized telomerase DNA vaccine in patients with advanced solid tumors: Final results of first-in-human phase I study

Abstract Background INVAC-1 is an optimized DNA plasmid encoding an inactive form of human Telomerase Reverse Transcriptase (hTERT), a universal tumor antigen expressed in most of human tumors with little or no expression in normal somatic cells. Primary pharmacodynamics, safety and toxicology studies showed that INVAC-1 was enzymatically inactive, immunogenically safe and well tolerated. In murine models, we demonstrated that INVAC-1 was able to induce hTERT specific cellular immune responses with CD4+ Th1 effector and memory CD8+ T-cells as well as slow tumor growth and increase survival rate by 50% in tumor-bearing mice. Methods We conducted a First-In-Human (FIH) study, 2-centre, Phase I, open label, 3+3 escalation design and multiple dose study examining the safety and tolerability of INVAC-1 administered at three dose levels (100, 400 and 800 µg) in 26 patients with relapsed or solid refractory tumors. INVAC-1 was administered either by intradermal (ID) injection followed by electroporation (EP) (n=20) or by Tropis® Needle Free Injection System (n=6). Results INVAC-1 vaccination was safe and well tolerated when administered ID (either with EP or by Tropis®) at the three tested doses. Only one treatment-related grade 3 SAE was reported. 58% of patients experienced disease stabilization up to 9.9 months. One-year survival was reached for 65% of patients. INVAC-1 elicited both hTERT specific Th1-dominant CD4 and cytotoxic CD8 T cell responses with no vaccine-induced peripheral immunosuppression. Anti-hTERT immune responses were enhanced by adding anti-PD-1 immune checkpoint inhibitor ex vivo. In addition, INVAC-1 vaccination was able to promote epitope spreading. Finally, correlation analysis between clinical and immunological data showed that patients with OS >1 year presented a significantly higher hTERT immune response after INVAC-1 vaccination compared to patients with OS <1 year. Moreover, estimated median OS in INVAC-1 immune responders was 17.4 months vs. 7 months for non-responders. Conclusion INVAC-1 vaccination was safe, well tolerated and immunogenic when administered ID at the three tested doses. Disease stabilization was observed for the majority of patients during the treatment period and beyond. Clinical trial identification #NCT02301754 Citation Format: Julie Garibal, Jacques Medioni, Luis Teixeira, Olivier Adotevi, Marie-Agnès Dragon-Durey, Caroline Laheurte, Claire Germain, Marie Escande, Maria Wehbe, Valérie Doppler, Thierry Huet, Pierre Langlade Demoyen. INVAC-1, an optimized telomerase DNA vaccine in patients with advanced solid tumors: Final results of first-in-human phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT021.

Treg-Resistant Cytotoxic CD4+ T Cells Dictate T Helper Cells in Their Vicinity: TH17 Skewing and Modulation of Proliferation.

Cytotoxic CD4+ T cells (CD4 CTL) are terminally differentiated T helper cells that contribute to autoimmune diseases, such as multiple sclerosis. We developed a novel triple co-culture transwell assay to study mutual interactions between CD4 CTL, conventional TH cells, and regulatory T cells (Tregs) simultaneously. We show that, while CD4 CTL are resistant to suppression by Tregs in vitro, the conditioned medium of CD4 CTL accentuates the suppressive phenotype of Tregs by upregulating IL-10, Granzyme B, CTLA-4, and PD-1. We demonstrate that CD4 CTL conditioned medium skews memory TH cells to a TH17 phenotype, suggesting that the CD4 CTL induce bystander polarization. In our triple co-culture assay, the CD4 CTL secretome promotes the proliferation of TH cells, even in the presence of Tregs. However, when cell−cell contact is established between CD4 CTL and TH cells, the proliferation of TH cells is no longer increased and Treg-mediated suppression is restored. Taken together, our results suggest that when TH cells acquire cytotoxic properties, these Treg-resistant CD4 CTL affect the proliferation and phenotype of conventional TH cells in their vicinity. By creating such a pro-inflammatory microenvironment, CD4 CTL may favor their own persistence and expansion, and that of other potentially pathogenic TH cells, thereby contributing to pathogenic responses in autoimmune disorders.

Antigen-specific antibody and polyfunctional T cells generated by respiratory immunization with protective Burkholderia\u0394tonB\u0394hcp1 live attenuated vaccines

Melioidosis, caused by Burkholderia pseudomallei (Bpm), lacks a vaccine. We identify the immune correlates of protection induced by B. mallei ΔtonB Δhcp1 (CLH001) and Bpm ΔtonB Δhcp1 (PBK001) vaccines against inhalational melioidosis. Mucosal immunization with either vaccine generates Bpm-specific IgM and IgG (IgG2b/c > IgG1 > IgG3) antibodies in sera and lungs, and lung IgA antibodies. Sera confers complement-independent bactericidal activity and macrophages opsonophagocytic uptake but is insufficient in passive transfer experiments to provide significant protection. Both vaccines elicit memory Th1 and Th17 CD4+ T-cell responses in lung and spleen after Bpm antigen-specific recall. The PBK001 vaccine is superior in generating respiratory IgA post-boost, anamnestic IgG at challenge, T-cell recall to specific antigen, and development of diverse polyfunctional memory T-cell pools. Analysis of lung histology suggests that potent polyfunctional T-cell memory and/or IL-17 signatures generated with PBK001 vaccination may be associated with moderate lung inflammation post vaccination.

Removal of CD276+ cells from haploidentical memory T-cell grafts significantly lowers the risk of GVHD

Detrimental graft-versus-host disease (GVHD) still remains a major cause of death in hematopoietic stem cell transplantation (HSCT). The recently explored depletion of naive cells from mobilized grafts (CD45RA depletion) has shown considerable promise, yet is unable to eliminate the incidence of GVHD. Analysis of CD45RA-depleted haploidentical mixed lymphocytes culture (haplo-MLC) revealed insufficient suppression of alloresponses in the CD4+ compartment and identified CD276 as a marker for alloreactive memory Th1 T cells. Conclusively, depleting CD276+ cells from CD45RA-depleted haplo-MLC significantly attenuated alloreactivity to recipient cells while increasing antiviral reactivity and maintaining anti-third party reactivity in vitro. To evaluate these findings in vivo, bulk, CD45RA-depleted, or CD45RA/CD276-depleted CD4+ T cells from HLA-DR4negative healthy humans were transplanted into NSG-Ab°DR4 mice, a sensitive human allo-GVHD model. Compellingly, CD45RA/CD276-depleted grafts from HLA-DR4negative donors or in vivo depletion of CD276+ cells after transplant of HLA-DR4negative memory CD4 T cells significantly delay the onset of GVHD symptoms and significantly alleviate its severity in NSG-Ab°DR4 mice. The clinical courses correlated with diminished Th1-cytokine secretion and downregulated CXCR6 expression of engrafted peripheral T cells. Collectively, mismatched HLA-mediated GVHD can be controlled by depleting recipient-specific CD276+ alloreacting T cells from the graft, highlighting its application in haplo-HSCT.

Monocyte-Derived Dendritic Cells (moDCs) Differentiate into Bcl6+ Mature moDCs to Promote Cyclic di-GMP Vaccine Adjuvant-Induced Memory TH Cells in the Lung.

Induction of lung mucosal immune responses is highly desirable for vaccines against respiratory infections. We recently showed that monocyte-derived dendritic cells (moDCs) are responsible for lung IgA induction. However, the dendritic cell subset inducing lung memory TH cells is unknown. In this study, using conditional knockout mice and adoptive cell transfer, we found that moDCs are essential for lung mucosal responses but are dispensable for systemic vaccine responses. Next, we showed that mucosal adjuvant cyclic di-GMP differentiated lung moDCs into Bcl6+ mature moDCs promoting lung memory TH cells, but they are dispensable for lung IgA production. Mechanistically, soluble TNF mediates the induction of lung Bcl6+ moDCs. Our study reveals the functional heterogeneity of lung moDCs during vaccination and paves the way for an moDC-targeting vaccine strategy to enhance immune responses on lung mucosa.

IL-23 maintains tissue resident memory Th17 cells in murine and psoriatic skin

Abstract Tissue resident memory Th17 cells (TRM17) are the key cell type driving the chronic skin inflammation of psoriasis. Although IL-23 is strongly associated with autoimmunity and chronic inflammatory disorders including psoriasis, and anti-IL-23 biologic agents have remarkable efficacy in the treatment of psoriasis, the precise role of IL-23 in supporting IL-17-mediated skin inflammation remains unclear. In mice, we found that circulating memory T cells were dispensable for anamnestic protection from C. albicans skin infection, and TRM17 mediated protection from C. albicans reinfection required IL-23. Administration of anti-IL-23R antibody to dual Il17aCre Rosa26CAG-fl/fl-tdTomato Il17fThy1.1/Thy1.1 (17Fate) fate reporter mice following resolution of primary C. albicans infection resulted in a selective reduction in the number of CD69+CD103+TRM17 cells in skin compared with isotype controls. TRM17 proliferation was reduced and survival was unaffected. CD301b+ dermal dendritic cells (dDC) were an obligate source of IL-23 that supported TRM17 maintenance in skin after C. albicans challenge. These data demonstrate that locally produced IL-23 promotes in situ TRM17 proliferation to support their long term retention in skin. In normal human skin, we identified dermal cDC2 as the principal source of IL-23, although keratinocytes and CD4+ T cells were additional sources of IL-23 in psoriasis skin. Analysis of human psoriasis skin before and after clinical anti-IL-23 therapy revealed reduced TRM17 number and proliferation index, suggesting that targeted depletion of pathogenic TRM17 is the major mechanism by which anti-IL-23 therapy induces uniquely durable disease-free intervals in psoriasis patients.

NLRP1 acts as a negative regulator of Th17 cell programming in mice and humans with autoimmune diabetes.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic β cells. We show here that the protein NOD-like receptor family pyrin domain containing 1 (NLRP1) has a key role in the pathogenesis of mouse and human T1D. More specifically, downregulation of NLRP1 expression occurs during T helper 17 (Th17) differentiation, alongside greater expression of several molecules related to Th17 cell differentiation in a signal transducers and activators of transcription 3 (STAT3)-dependent pathway. These changes lead to a consequent increase in interleukin 17 (IL-17) production within the pancreas and higher incidence of diabetes in streptozotocin (STZ)-injected mice. Finally, in patients with T1D and a SNP (rs12150220) in NLRP1, there is a robust decrease in IL-17 levels in serum and in memory Th17 cells from peripheral blood mononuclear cells. Our results demonstrate that NLRP1 acts as a negative regulator of the Th17 cell polarization program, making it an interesting target for intervention during the early stages of T1D.

036 IL-23 maintains tissue resident memory Th17 cells in murine and psoriatic skin

036 IL-23 maintains tissue resident memory Th17 cells in murine and psoriatic skin

A single nucleotide polymorphism in the gene for GPR183 increases its surface expression on blood lymphocytes of patients with inflammatory bowel disease.

Background and PurposeSingle nucleotide polymorphism rs9557195 within the gene of the G protein‐coupled receptor Epstein‐Barr virus‐induced gene 2 (EBI2/GPR183) has been associated with increased risk for inflammatory bowel diseases (IBD). GPR183 mediates the migration of intestinal immune cells and promotes colitis in animal models. Here, we study GPR183 surface expression of immune cells and associations of rs9557195 with GPR183 expression and IBD disease course.Experimental ApproachWe recruited 27 IBD patients (15 with ulcerative colitis [UC] and 12 with Crohn's disease [CD]) and eight healthy volunteers (HV). GPR183 expression was measured by FACS in subtypes of peripheral blood mononuclear cells. We analysed IBD disease course in 2301 patients (1335 with CD and 966 with UC) of the Swiss IBD cohort study.Key ResultsWe found increased GPR183 expression in lymphocytes expressing chemokine receptors CCR6 or CCR9, implicated in IBD and on Th17 memory T cells. The GPR183 ligand 7α,25‐dihydroxycholesterol and the CCR6 ligand CCL20 stimulated migration of memory T cells in an additive manner. Further, IBD patients with the CC allele of rs9557195 had higher GPR183 surface expression compared to individuals with the TT allele. Swiss IBD cohort study patients carrying the rs9557195‐CC allele had higher psoriasis rates compared to individuals with the TT allele.Conclusion and ImplicationsWe demonstrate increased GPR183 surface expression on T cells with a potential role in gut inflammation. An SNP of the GPR183 locus was associated with GPR183 surface expression and psoriasis rates in IBD patients. Our data suggest a pro‐inflammatory role of GPR183 in IBD.LINKED ARTICLESThis article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc

CCR4 Involvement in the Expansion of T Helper Type 17 Cells in a Mouse Model of Psoriasis

Psoriasis is a chronic skin disease associated with T helper (Th)17-mediated inflammation. Because CCR4 is a major chemokine receptor expressed on Th17 cells, we investigated the role of CCR4 in a modified imiquimod-induced psoriasis model that showed enhanced skin infiltration of Th17 cells. CCR4-deficient mice had less severe skin disease than wild-type mice. Th17 cells were decreased in the skin lesions and regional lymph nodes of CCR4-deficient mice. In the regional lymph nodes of wild-type mice, CD44+ memory Th17 cells expressing CCR4 were found to be clustered with dendritic cells expressing CCL22, a ligand for CCR4. Such dendritic cell‒Th17 cell clusters were significantly decreased in CCR4-deficient mice. Similar results were obtained using the IL-23‒induced psoriasis model. Invitro, compound 22, a CCR4 antagonist, significantly reduced the expansion of Th17 cells in the coculture of CD11c+ dendritic cells and CD4+ T cells separately prepared from the regional lymph nodes of wild-type mice with psoriasis. Invivo, compound 22 ameliorated the psoriasis-like skin disease in wild-type mice with significant decreases of Th17 cells in the regional lymph nodes and skin lesions. Collectively, CCR4 is likely to play a role in the pathogenesis of psoriasis through the expansion of Th17 cells.

Clarithromycin impairs tissue-resident memory and Th17 responses to macrolide-resistant Streptococcus pneumoniae infections

The increasing prevalence of antimicrobial resistance in pathogens is a growing public health concern, with the potential to compromise the success of infectious disease treatments in the future. Particularly, the number of infections by macrolide antibiotics-resistant Streptococcus pneumoniae is increasing. We show here that Clarithromycin impairs both the frequencies and number of interleukin (IL)-17 producing T helper (Th) 17 cells within the lungs of mice infected with a macrolide-resistant S. pneumoniae serotype 15A strain. Subsequently, the tissue-resident memory CD4+ T cell (Trm) response to a consecutive S. pneumoniae infection was impaired. The number of lung resident IL-17+ CD69+ Trm was diminished upon Clarithromycin treatment during reinfection. Mechanistically, Clarithromycin attenuated phosphorylation of the p90-S6-kinase as part of the ERK pathway in Th17 cells. Moreover, a strong increase in the mitochondrial-mediated maximal respiratory capacity was observed, while mitochondrial protein translation and mTOR sisgnaling were unimpaired. Therefore, treatment with macrolide antibiotics may favor the spread of antimicrobial-resistant pathogens not only by applying a selection pressure but also by decreasing the natural T cell immune response. Clinical administration of macrolide antibiotics as standard therapy procedure during initial hospitalization should be reconsidered accordingly and possibly be withheld until microbial resistance is determined.Key messages• Macrolide-resistant S. pneumoniae infection undergoes immunomodulation by Clarithromycin• Clarithromycin treatment hinders Th17 and tissue-resident memory responses• Macrolide antibiotics impair Th17 differentiation in vitro by ERK-pathway inhibition

Suppression of mucosal Th17 memory responses by acellular pertussis vaccines enhances nasal Bordetella pertussis carriage

Pertussis has made a spectacular rebound in countries that have switched from whole-cell (wPV) to acellular pertussis vaccines (aPV). Here, we show that, unlike wPV, aPV, while protective against lung colonization by Bordetella pertussis (Bp), did not protect BALB/c mice from nasal colonization, but instead substantially prolonged nasal carriage. aPV prevented the natural induction of nasal interleukin-17 (IL-17)-producing and interferon-γ (IFN-γ)-producing CD103+ CD44+ CD69+ CD4+-resident memory T (TRM) cells. IL-17-deficient, but not IFN-γ-deficient, mice failed to clear nasal Bp, indicating a key role of IL-17+ TRM cells in the control of nasal infection. These cells appeared essential for neutrophil recruitment, crucial for clearance of Bp tightly bound to the nasal epithelium. Transfer of IL-17+ TRM cells from Bp-infected mice to IL-17-deficient mice resulted in neutrophil recruitment and protection against nasal colonization. Thus, aPV may have augmented the Bp reservoir by inhibiting natural TRM cell induction and neutrophil recruitment, thereby contributing to the pertussis resurgence.

Genetic and pharmacological inhibition of the nuclear receptor ROR\u03b1 regulates TH17 driven inflammatory disorders

Full development of IL-17 producing CD4+ T helper cells (TH17 cells) requires the transcriptional activity of both orphan nuclear receptors RORα and RORγt. However, RORα is considered functionally redundant to RORγt; therefore, the function and therapeutic value of RORα in TH17 cells is unclear. Here, using mouse models of autoimmune and chronic inflammation, we show that expression of RORα is required for TH17 cell pathogenicity. T-cell-specific deletion of RORα reduces the development of experimental autoimmune encephalomyelitis (EAE) and colitis. Reduced inflammation is associated with decreased TH17 cell development, lower expression of tissue-homing chemokine receptors and integrins, and increased frequencies of Foxp3+ T regulatory cells. Importantly, inhibition of RORα with a selective small molecule antagonist mostly phenocopies our genetic data, showing potent suppression of the in vivo development of both chronic/progressive and relapsing/remitting EAE, but with no effect on overall thymic cellularity. Furthermore, use of the RORα antagonist effectively inhibits human TH17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORα functions independent of RORγt in programming TH17 pathogenicity and identifies RORα as a safer and more selective therapeutic target for the treatment of TH17-mediated autoimmunity.

Estradiol Enhances Antiviral CD4+Tissue-Resident Memory T Cell Responses following Mucosal Herpes Simplex Virus 2 Vaccination through an IL-17-Mediated Pathway

Estradiol (E2) is a sex hormone which has been shown to be protective against sexually transmitted infections such as herpes simplex virus 2 (HSV-2). However, few studies have examined the underlying mechanisms by which this occurs. Here, we investigated the effect of E2 on the establishment of memory T cells post-intranasal immunization with HSV-2. CD4+ T cell responses first appeared in the upper respiratory tract (URT) within 3 days postimmunization before being detected in the female reproductive tract (FRT) at 7 days. E2 treatment resulted in greater and earlier Th17 responses, which preceded augmented Th1 responses at these sites. The CD4+ T cells persisted in the URT for up to 28 days, and E2 treatment resulted in higher frequencies of memory T cells. Intranasal immunization also led to the establishment of CD4+ tissue-resident memory T cells (TRM cells) in the FRT, and E2 treatment resulted in increased Th1 and Th17 TRM cells. When the migration of circulating T cells into the FRT was blocked by FTY720, immunized E2-treated mice remained completely protected against subsequent genital HSV-2 challenge compared to non-E2 controls, confirming that TRM cells alone are adequate for protection in these mice. Finally, the enhanced vaginal Th1 TRM cells present in E2-treated mice were found to be modulated through an interleukin 17 (IL-17)-mediated pathway, as E2-treated IL-17A-deficient mice had impaired establishment of Th1 TRM cells. This study describes a novel role for E2 in enhancing CD4+ memory T cells and provides insight on potential strategies for generating optimal immunity during vaccination.IMPORTANCE Herpes simplex virus 2 (HSV-2) is a highly prevalent sexually transmitted infection for which there is currently no vaccine available. Interestingly, the female sex hormone estradiol has been shown to be protective against HSV-2. However, the underlying mechanisms by which this occurs remains relatively unknown. Our study demonstrates that under the influence of estradiol treatment, intranasal immunization with an attenuated strain of HSV-2 leads to enhanced establishment of antiviral memory T cell responses in the upper respiratory tract and female reproductive tract. In these sites, estradiol treatment leads to greater Th17 memory cells, which precede enhanced Th1 memory responses. Consequently, the T cell responses mounted by tissue-resident memory cells in the female reproductive tract of estradiol-treated mice are sufficient to protect mice against vaginal HSV-2 challenge. This study offers important insights regarding the regulation of mucosal immunity by hormones and on potential strategies for generating optimal immunity during vaccination.

Interleukin-25-mediated resistance against intestinal trematodes does not depend on the generation of Th2 responses

BackgroundThe cytokine interleukin-25 (IL-25) is recognized as the most relevant initiator of protective T helper 2 (Th2) responses in intestinal helminth infections. This cytokine induces resistance against several species of intestinal helminths, including the trematode Echinostoma caproni. E. caproni has been extensively used as an experimental model to study the factors determining resistance to intestinal infections. In the study reported here, we assessed the role of IL-25 in the generation of resistance in mice infected with E. caproni.MethodsThe factors that determine the production of IL-25 in mice experimentally infected with E. caproni were determined, as were the consequences of IL-25 production in terms of polarization of the immune response and resistance to infection.ResultsOur results show that the role of IL-25 in the polarization of the immune response differs between the primary and secondary immune responses. IL-25 is required for the development of a Th2 phenotype in primary E. caproni infections, but it can also promote the differentiation to Th2 memory cell subsets that enhance type-2 immunity in memory responses. However, the development of Th2 responses does not induce resistance to infection. The Th2 phenotype does not elicit resistance, and IL-25 is responsible for the resistance regardless of its type-2 cytokine activity and activation of signal transducer and activator of transcription (STAT6). Alternative activation of macrophages induced by IL-25 can be implicated in the resistance to infection.ConclusionsIn contrast to primary infection, secondary infection elicits a type-2 immune response even in the absence of IL-25 expression. Despite the development of a type-2 response, mice are susceptible to secondary infection associated with the lack of IL-25. Resistance to infection is due to the production of IL-25, which acts autonomously from Th2 response in terms of parasite clearance.Graphical

Flu Virus Attenuates Memory Clearance of Pneumococcus via IFN-γ-Dependent Th17 and Independent Antibody Mechanisms.

SummaryBacterial coinfection is a major cause of influenza-associated mortality. Most people have experienced infections with bacterial pathogens commonly associated with influenza A virus (IAV) coinfection before IAV exposure; however, bacterial clearance through the immunological memory response (IMR) in coinfected patients is inefficient, suggesting that the IMR to bacteria is impaired during IAV infection. Adoptive transfer of CD4+ T cells from mice that had experienced bacterial infection into IAV-infected mice revealed that memory protection against bacteria was weakened in the latter. Additionally, memory Th17 cell responses were impaired due to an IFN-γ-dependent reduction in Th17 cell proliferation and delayed migration of CD4+ T cells into the lungs. A bacterium-specific antibody-mediated memory response was also substantially reduced in coinfected mice, independently of IFN-γ. These findings provide additional perspectives on the pathogenesis of coinfection and suggest additional strategies for the treatment of defective antibacterial immunity and the design of bacterial vaccines against coinfection.

Characterization of Clinical and Immune Responses in an Experimental Chronic Autoimmune Uveitis Model

Autoimmune uveitis is a sight-threatening intraocular inflammatory disease. For >30 years, the mouse model of experimental autoimmune uveitis has been employed to investigate disease mechanisms and test immunotherapeutic approaches. However, inflammation in this model is self-limited, and does not replicate the chronic, insidious nature prevalent in the human disease. Herein, a robust and reliable model of chronic autoimmune uveitis was developed and characterized in two strains of wild-type mice by modifying interphotoreceptor retinoid-binding protein dose and peptide fragments from conventional experimental autoimmune uveitis models. In both of these murine strains, immunization with our modified protocols resulted in a slowly progressive uveitis, with retinal scars and atrophy observed in the chronic stage by fundoscopy. Optical coherence tomography demonstrated decreased retinal thickness in chronic autoimmune uveitis mice, and electroretinography showed significantly reduced amplitudes of dark-adapted a- and b-waves and light-adapted b-waves. Histologic examination revealed prominent choroiditis with extensive retinal damage. Flow cytometry analysis showed substantially increased numbers of CD44hiIL-17+IFN-γ- memory T-helper 17 (Th17) cells in the retina, cervical lymph nodes, inguinal lymph nodes, and spleen. These data establish new modified protocols for inducing chronic uveitis in wild-type mice, and demonstrate a predominant memory Th17 cell response, suggesting an important role for memory Th17 cells in driving chronic inflammation in autoimmune uveitis.

Th1 concomitant immune response mediated by IFN-γ protects against sand fly delivered Leishmania infection: Implications for vaccine design

Leishmaniasis is an unresolved global health problem with a high socio-economic impact. Data generated in mouse models has revealed that the Th1 response, with IL-12, IFN-γ, TNF-α, and IL-2 as prominent cytokines, predominantly controls the disease progression. Premised on these findings, all examined vaccine formulations have been aimed at generating a long-lived memory Th1 response. However, all vaccine formulations with the exception of live Leishmania inoculation (leishmanization) have failed to sufficiently protect against sand fly delivered infection. It has been recently unraveled that sand fly dependent factors may compromise pre-existing Th1 memory. Further scrutinizing the immune response after leishmanization has uncovered the prominent role of early (within hours) and robust IFN-γ production (Th1 concomitant immunity) in controlling the sand fly delivered secondary infection. The response is dependent upon parasite persistence and subclinical ongoing primary infection. The immune correlates of concomitant immunity (Resident Memory T cells and Effector T subsets) mitigate the early effects of sand fly delivered infection and help to control the disease. In this review, we have described the early events after sand fly challenge and the role of Th1 concomitant immunity in the protective immune response in leishmanized resistant mouse model, although leishmanization is under debate for human use. Undoubtedly, the lessons we learn from leishmanization must be further implemented in alternative vaccine approaches.

The role of TH17 cells in multiple sclerosis: Therapeutic implications.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) where immunopathology is thought to be mediated by myelin-reactive CD4+ T helper (TH) cells. The TH cells most commonly implicated in the pathogenesis of the disease are of TH1 and TH17 lineage, which are defined by the production of interferon-γ and interleukin-17, respectively. Moreover, there is emerging evidence for the involvement of TH17.1 cells, which share the hallmarks of TH1 and TH17 subsets. In this review, we summarise current knowledge about the potential role of TH17 subsets in the initiation and progression of the disease and put a focus on their response to approved immunomodulatory MS drugs. In this regard, TH17 cells are abundant in peripheral blood, cerebrospinal fluid and brain lesions of MS patients, and their counts and inflammatory mediators are further increased during relapses. Fingolimod and alemtuzumab induce a paramount decrease in central memory T cells, which harbour the majority of peripheral TH17 cells, while the efficacy of natalizumab, dimethyl fumarate and importantly hematopoietic stem cell therapy correlates with TH17.1 cell inhibition. Interestingly, also CD20 antibodies target highly inflammatory TH cells and hamper TH17 differentiation by IL-6 reductions. Moreover, recovery rates of TH cells best correlate with long-term efficacy after therapeutical immunodepletion. We conclude that central memory TH17.1 cells play a pivotal role in MS pathogenesis and they represent a major target of MS therapeutics.

New MoDC-Targeting TNF Fusion Proteins Enhance Cyclic Di-GMP Vaccine Adjuvanticity in Middle-Aged and Aged Mice

Cyclic dinucleotides (CDNs) are promising vaccine adjuvants inducing balanced, potent humoral, and cellular immune responses. How aging influences CDN efficacy is unclear. We examined the vaccine efficacy of 3′,5′-cyclic diguanylic acid (cyclic di-GMP, CDG), the founding member of CDNs, in 1-year-old (middle-aged) and 2-year-old (aged) C57BL/6J mice. We found that 1- and 2-year-old C57BL/6J mice are defective in CDG-induced memory T helper (Th)1 and Th17 responses and high-affinity serum immunoglobulin (Ig)G, mucosal IgA production. Next, we generated two novel tumor necrosis factor (TNF) fusion proteins that target soluble TNF (solTNF) and transmembrane TNF (tmTNF) to monocyte-derived dendritic cells (moDCs) to enhance CDG vaccine efficacy in 1- and 2-year-old mice. The moDC-targeting TNF fusion proteins restored CDG-induced memory Th1, Th17, and high-affinity IgG, IgA responses in the 1- and 2-year-old mice. Together, the data suggested that aging negatively impacts CDG vaccine adjuvanticity. MoDC-targeting TNF fusion proteins enhanced CDG adjuvanticity in the aging mice.