scholarly journals The Effects of Interferons on Allogeneic T Cell Response in GVHD: The Multifaced Biology and Epigenetic Regulations

2021 ◽  
Vol 12 ◽  
Author(s):  
Chenchen Zhao ◽  
Yi Zhang ◽  
Hong Zheng
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Type I ◽  
Epigenetic Mechanisms ◽  
Hematopoietic Stem ◽  
Cell Responses ◽  
Alloreactive T Cells ◽  
And Function ◽  
Alloreactive T Cell

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. This beneficial effect is derived mainly from graft-versus-leukemia (GVL) effects mediated by alloreactive T cells. However, these alloreactive T cells can also induce graft-versus-host disease (GVHD), a life-threatening complication after allo-HSCT. Significant progress has been made in the dissociation of GVL effects from GVHD by modulating alloreactive T cell immunity. However, many factors may influence alloreactive T cell responses in the host undergoing allo-HSCT, including the interaction of alloreactive T cells with both donor and recipient hematopoietic cells and host non-hematopoietic tissues, cytokines, chemokines and inflammatory mediators. Interferons (IFNs), including type I IFNs and IFN-γ, primarily produced by monocytes, dendritic cells and T cells, play essential roles in regulating alloreactive T cell differentiation and function. Many studies have shown pleiotropic effects of IFNs on allogeneic T cell responses during GVH reaction. Epigenetic mechanisms, such as DNA methylation and histone modifications, are important to regulate IFNs’ production and function during GVHD. In this review, we discuss recent findings from preclinical models and clinical studies that characterize T cell responses regulated by IFNs and epigenetic mechanisms, and further discuss pharmacological approaches that modulate epigenetic effects in the setting of allo-HSCT.

scholarly journals B cell depletion impairs vaccination-induced CD8+ T cell responses in a type I interferon-dependent manner

2021 ◽  
pp. annrheumdis-2021-220435
Author(s):  
Theresa Graalmann ◽  
Katharina Borst ◽  
Himanshu Manchanda ◽  
Lea Vaas ◽  
Matthias Bruhn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Expansion ◽  
De Novo ◽  
T Cell Responses ◽  
Type I ◽  
Cell Responses ◽  
T Cell Expansion

ObjectivesThe monoclonal anti-CD20 antibody rituximab is frequently applied in the treatment of lymphoma as well as autoimmune diseases and confers efficient depletion of recirculating B cells. Correspondingly, B cell-depleted patients barely mount de novo antibody responses during infections or vaccinations. Therefore, efficient immune responses of B cell-depleted patients largely depend on protective T cell responses.MethodsCD8+ T cell expansion was studied in rituximab-treated rheumatoid arthritis (RA) patients and B cell-deficient mice on vaccination/infection with different vaccines/pathogens.ResultsRituximab-treated RA patients vaccinated with Influvac showed reduced expansion of influenza-specific CD8+ T cells when compared with healthy controls. Moreover, B cell-deficient JHT mice infected with mouse-adapted Influenza or modified vaccinia virus Ankara showed less vigorous expansion of virus-specific CD8+ T cells than wild type mice. Of note, JHT mice do not have an intrinsic impairment of CD8+ T cell expansion, since infection with vaccinia virus induced similar T cell expansion in JHT and wild type mice. Direct type I interferon receptor signalling of B cells was necessary to induce several chemokines in B cells and to support T cell help by enhancing the expression of MHC-I.ConclusionsDepending on the stimulus, B cells can modulate CD8+ T cell responses. Thus, B cell depletion causes a deficiency of de novo antibody responses and affects the efficacy of cellular response including cytotoxic T cells. The choice of the appropriate vaccine to vaccinate B cell-depleted patients has to be re-evaluated in order to efficiently induce protective CD8+ T cell responses.

scholarly journals Alloreactive T Cell Responses and Acute Rejection of Single Class II MHC-Disparate Heart Allografts Are under Strict Regulation by CD4+CD25+ T Cells.

2005 ◽  
Vol 174 (8) ◽  
pp. 5135.2-5135 ◽  
Author(s):  
Soren Schenk ◽  
Danielle D. Kish ◽  
Chunshui He ◽  
Tarek El-Sawy ◽  
Eise Chiffoleau ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Acute Rejection ◽  
T Cell Responses ◽  
Class Ii ◽  
Single Class ◽  
Cell Responses ◽  
Class Ii Mhc ◽  
Strict Regulation ◽  
Alloreactive T Cell

scholarly journals The Subcellular Location of Ovalbumin in Plasmodium berghei Blood Stages Influences the Magnitude of T-Cell Responses

2014 ◽  
Vol 82 (11) ◽  
pp. 4654-4665 ◽  
Author(s):  
Jing-Wen Lin ◽  
Tovah N. Shaw ◽  
Takeshi Annoura ◽  
Aurélie Fougère ◽  
Pascale Bouchier ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Plasmodium Berghei ◽  
Parasitophorous Vacuole ◽  
T Cell Responses ◽  
Subcellular Location ◽  
Expression Level ◽  
Content Type ◽  
Cell Responses ◽  
And Function

ABSTRACTModel antigens are frequently introduced into pathogens to study determinants that influence T-cell responses to infections. To address whether an antigen's subcellular location influences the nature and magnitude of antigen-specific T-cell responses, we generatedPlasmodium bergheiparasites expressing the model antigen ovalbumin (OVA) either in the parasite cytoplasm or on the parasitophorous vacuole membrane (PVM). For cytosolic expression, OVA alone or conjugated to mCherry was expressed from a strong constitutive promoter (OVAhsp70orOVA::mCherryhsp70); for PVM expression, OVA was fused to HEP17/EXP1 (OVA::Hep17hep17). Unexpectedly, OVA expression inOVAhsp70parasites was very low, but when OVA was fused to mCherry (OVA::mCherryhsp70), it was highly expressed. OVA expression inOVA::Hep17hep17parasites was strong but significantly less than that inOVA::mCherryhsp70parasites. These transgenic parasites were used to examine the effects of antigen subcellular location and expression level on the development of T-cell responses during blood-stage infections. While all OVA-expressing parasites induced activation and proliferation of OVA-specific CD8+T cells (OT-I) and CD4+T cells (OT-II), the level of activation varied:OVA::Hep17hep17parasites induced significantly stronger splenic and intracerebral OT-I and OT-II responses than those ofOVA::mCherryhsp70parasites, butOVA::mCherryhsp70parasites promoted stronger OT-I and OT-II responses than those ofOVAhsp70parasites. Despite lower OVA expression levels,OVA::Hep17hep17parasites induced stronger T-cell responses than those ofOVA::mCherryhsp70parasites. These results indicate that unconjugated cytosolic OVA is not stably expressed inPlasmodiumparasites and, importantly, that its cellular location and expression level influence both the induction and magnitude of parasite-specific T-cell responses. These parasites represent useful tools for studying the development and function of antigen-specific T-cell responses during malaria infection.

scholarly journals Sting Negatively Regulates Allogeneic T-Cell Responses By Constraining Antigen-Presenting Cell Function

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-38
Author(s):  
Yongxia Wu ◽  
Chih-Hang Anthony Tang ◽  
Corey Mealer ◽  
David Bastian ◽  
Mohammed Hanief Sofi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Conflicts Of Interest ◽  
Hematopoietic Cells ◽  
T Cell Responses ◽  
Receptor Expression ◽  
Constitutive Activation ◽  
Cell Responses ◽  
And Function

The endoplasmic-reticulum-resident protein STING (Stimulator of IFN genes) is a downstream signaling effector of cytosolic DNA sensor cGAS (cyclic GMP-AMP synthase). STING-mediated innate immune activation plays a key role in tumor- and self-DNA elicited anti-tumor immunity and autoimmunity, respectively, yet the mechanism remains largely unclear. We utilized murine models of allogeneic hematopoietic cell transplantation (allo-HCT) to study the biology of STING in antigen-presetting cells (APCs) and T cells. STING expression in donor T cells was dispensable for their ability to induce graft-versus-host disease (GVHD), a major complication of allo-HCT in the clinic. However, when STING-deficient mice were used as recipients, more severe disease was induced after allo-HCT. Using bone marrow (BM) chimeras where STING was absent in different compartments, we found that STING-deficiency on host hematopoietic cells (Fig. A), but not on non-hematopoietic cells, was primarily responsible for exacerbating the disease. Furthermore, STING expression on host CD11c+ cells played a dominant role in the regulation of allogeneic T-cell responses (Fig. B). Mechanistically, STING deficiency resulted in increased survival, activation and function of irradiated APCs, including macrophages and dendritic cells (DCs, fig. C-D). To further determine the role of STING in APCs, we generated a STING V154M knock-in mouse model, in which V154M mutation in TMEM173 causes constitutive activation of STING. Consistently, constitutive activation of STING attenuated the survival, activation and function of APCs isolated from STING V154M knock-in mice. In addition, STING-deficient APCs augmented donor T-cell expansion, chemokine receptor expression and migration into intestinal tissues (Fig. E), resulting in accelerated/exacerbated disease. Using pharmacologic approaches, we demonstrate that systemic administration of a STING agonist (c-di-GMP) to recipient mice before transplantation significantly reduced GVHD mortality (Fig. F). In conclusion, we report an inhibitory role of STING in regulating survival and T-cell priming function of hematopoietic APCs, especially CD11c+ cells, after allo-HCT. We validate that pharmacological activation of STING may serve as a potential therapeutic strategy to constrain APCs and induce immune tolerance. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals Control of T Cell Responses, Tolerance and Autoimmunity by Regulatory T Cells: Current Concepts

2003 ◽  
Vol 46 (4) ◽  
pp. 131-137 ◽  
Author(s):  
Pavel Chrobák
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Viral Infections ◽  
T Cell Responses ◽  
Cell Responses ◽  
Chronic Viral Infections ◽  
And Function ◽  
Special Circumstances ◽  
Immunosuppressive Cytokines

Regulatory T cells have emerged as an important mechanism of regulating tolerance and T cell responses. CD4+ regulatory T cells can be divided into two main groups, natural regulatory T cells, which express high levels of CD25 on their cell surface and phenotypically diverse adaptive (antigen induced) regulatory T cells. Natural regulatory T cells are made in the thymus, and require strong costimulatory signals for induction and maintenance, express a transcription factor called Foxp3, and function by a largely unknown mechanism. Adaptive (antigen induced) regulatory T cells are made by sub-optimal antigenic signals in the periphery, in the presence of immunosuppressive cytokines, often in special circumstances, such as chronic viral infections or after mucosal administration of antigen, and rely on cytokines such as IL-10 and TGF-β for suppression. Regulatory T cells offer a great potential for the treatment of autoimmune diseases and during transplantation.

Spectratype Analysis of In Vitro Donor Anti-Host T Cell Repertoire Responses Predict Those of In Vivo Post-BMT.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2163-2163
Author(s):  
Thea M. Friedman ◽  
Kira Goldgirsh ◽  
Jenny Zilberberg ◽  
Stephanie A. Berger ◽  
Joanne Filicko-O’Hara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Post Transplant ◽  
Cell Responses ◽  
Repertoire Analysis ◽  
Alloreactive T Cell

Abstract Immunotherapeutic strategies have gained recognition as viable alternatives to more conventional modalities for the treatment of cancer. In this regard, adoptive T cell therapy through allogeneic blood and marrow transplantation (BMT) has provided the strongest evidence that anti-tumor effects could be achieved against hematological malignancies. However, the major complications of BMT still include graft failure, opportunistic infections, disease relapse and graft-versus-host disease (GVHD). The presence of mature donor T cells in the transplant inoculum reduces the incidence of the first three complications, while unfortunately increasing the risk of GVHD, which can be directed against either HLA or minor histocompatibilty antigen (miHA) disparities. Thus, a major objective in the field has been to develop tactics that could facilitate the separation of graft-versus-tumor (GVT) effects from the deleterious effects of GVHD. One such approach would be to selectively deplete donor alloreactive T cells in the donor inoculum while allowing residual T cells to provide some protection against infection and to support a tumor-specific GVT response. For a more targeted approach, delayed donor lymphocyte infusion (DLI) of positively-selected donor GVT-reactive T cells could be used weeks to months post-transplant, if these elements were identifiable. In this regard, TCR Vβ repertoire analysis by CDR3-size spectratyping can be a powerful tool for the characterization of alloreactive T cell responses. Theoretically, molecular analysis of T cell responses in vitro, given the high sensitivity of the PCR-based spectratyping technique, should identify the most potentially critical Vβ families involved in the later development of GVHD and GVT effects in patients. To this end, we tested the hypothesis that T cell repertoire analysis of HLA-matched sibling (SIB) or matched unrelated donors (URD) from in vitro, host-stimulated, mixed lymphocyte cultures (MLC) would be predictive of the TCR-Vβ spectratype analysis of the T cell repertoire in the patient following BMT. In this study, we examined 17 patient pairs and report that for the resolvable Vβ families, we observed overall 71.2 ± 11.9% (mean ± SD.; range 40%–85%) of the in vitro anti-host T cell responses were predictive of those in the patient post-transplant. Of the 28.8% non-predictive Vβ families, 6.9 ± 6.3% (range 0%–27%) exhibited skewing in the MLC but no skewing in the patient post-transplant repertoire, 9.3 ± 6.3% (range 0%–18.8%) exhibited skewing in different peaks within the same Vβ family, and 12.5 ± 10.8% (range 0%–40%) showed skewing in the patient post-transplant and none in the MLC. Taken together, these results suggest that the in vitro MLC T cell responses show good consistency with post-transplant patient responses. Thus, in vitro spectratyping may be useful for predicting the alloreactive T cell responses involved in GVHD and could be used to guide custom-designed select Vβ family T cell-depleted transplants to improve patient outcomes. The additional advantage of this approach is that minimization of GVHD risk can be obtained without any direct knowledge of the specific miHA involved in the individual donor-patient pair.

146 Alloantigen-specific Tr1 cells designed to prevent GvHD have a distinct molecular identity and suppress through CTLA-4 and PD-1

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A159-A159
Author(s):  
Alma-Martina Cepika ◽  
Pauline P Chen ◽  
Molly Uyeda ◽  
Brandon Cieniewicz ◽  
Mansi Narula ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Healthy Donor ◽  
Hematological Malignancies ◽  
T Cell Responses ◽  
Attractive Alternative ◽  
Hematopoietic Stem ◽  
Cell Responses ◽  
Tr1 Cells

BackgroundGraft-vs-host-disease (GvHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), limiting the use of this potentially curative treatment for hematological malignancies. To address this, we have developed T-allo10 cell therapy, which is enriched with type 1 regulatory T (Tr1) cells. Tr1 cells are peripherally inducible, CD49b+LAG3+IL-10+FOXP3- regulatory T cells that can confer alloantigen-specific tolerance, making them an attractive alternative to existing GvHD therapies, which non-discriminately impair both GvHD and protective immunity. T-allo10 cells are currently being evaluated in a phase I clinical trial in patients with hematological malignancies undergoing allo-HSCT (NCT03198234). Herein, we aimed to confirm that Tr1 cells are the active ingredient responsible for the T-allo10 suppressive function, and reveal the underlying molecular signatures to elucidate the mechanisms of Tr1 cell-mediated suppression.MethodsT-allo10 cells were generated in a co-culture of healthy host or patient tolerogenic dendritic cells (DC-10) with allogeneic healthy donor CD4+ T cells, then tested for Tr1 phenotype, anergy, suppression and cytokine production. Sorted T-allo10-derived Tr1 cells and non-Tr1 cells, as well as control effector T cells (Teff) and parental CD4+ T cells, were analyzed by TCR- and RNA-seq. Protein expression for key differentially expressed genes were validated, and the functional roles for IL-10, CTLA-4 and PD-1 in T-allo10-mediated suppression were confirmed in a suppression assay.ResultsWe show that the T-allo10 cell product is: i) enriched for Tr1 cells, ii) anergic in response to alloantigen re-challenge, but not to non-specific stimuli or 3rd party antigens, and iii) suppresses host-reactive T cells, but not T cell responses to other antigens. Furthermore, T-allo10-derived, isolated Tr1 cells had a restricted TCR repertoire, suggesting they clonally expand in response to alloantigens. T-allo10-derived Tr1 cells have a distinct signature compared to non-Tr1 cells, and, in addition to IL-10, express high levels of CTLA-4 and PD-1 (but not FOXP3). Notably, blockade of CTLA-4 and the PD-1 pathway completely abolishes T-allo10-mediated suppression of T cell responses.ConclusionsOur data shows that Tr1 cells are the active, suppressive, and antigen-specific ingredient of T-allo10 cells. Furthermore, while the role of IL-10 in Tr1 cell-mediated suppression is well known, we uncover that Tr1 suppress in addition through CTLA-4 and PD-1. Collectively, these intriguing findings underscore the importance of CTLA-4 and PD-1 pathways in conferring cell-mediated immunological tolerance. Further, they define the key characteristics and modes of action of antigen-specific Tr1 cells, providing crucial information for the ongoing T-all10 trial and future design of novel Tr1 cell-based therapies.Ethics ApprovalThe patient study was approved by Administrative Panels on Human Subjects in Medical Research, Stanford University, Tallo10 eProtocol # 38734. Healthy donor samples were purchased as deidentified human blood products from the Stanford Blood Center, and are thus exempt.

scholarly journals Novel Immunosuppressive Approach Attenuates Severe Aplastic Anemia in Mouse Lymphocyte Infusion AA Models

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2942-2942
Author(s):  
Jessica Lorente ◽  
Divya Kannegenti ◽  
Brandon Theall ◽  
Lisandra Hernandez ◽  
Esha Vallabhaneni ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Aplastic Anemia ◽  
Mouse Models ◽  
T Cell Responses ◽  
Effector T Cells ◽  
Hematopoietic Stem ◽  
Cell Responses ◽  
Mouse Lymphocyte

Abstract Aplastic Anemia (AA) is an immune-mediated and life-threatening form of acquired bone marrow failure. AA ranges from moderate to severe AA, and is characterized by development and expansion of self-reactive effector T cells, which cause apoptosis of mature blood cells, progenitors and hematopoietic stem cells (HSCs). Current treatments for AA, which are not always effective or feasible, include immunosuppressive therapy (IST) and allogeneic HLA-identical sibling or well-matched unrelated donor BM transplant. Because the self-antigens triggering AA remain to be identified, mouse lymphocyte infusion models of AA with striking similarities to human AA have been developed utilizing alloantigen recognition. The AA in these models is induced by infusing lymph node cells (LNCs) from C57BL/6J mice into MHC partially mismatched F1 hybrid B6D2F1 or CByB6F1 recipients, or into minor-H antigen mismatched C.B10 recipients. The host mice develop SAA without any clinical signs of generalized GVHD, and characterized by BM infiltration and oligoclonal expansion of donor effector T cells, apoptosis of all host BM cells, severe BM aplasia and death within 3-5 weeks after LNC infusion. These preclinical mouse models represent a very useful in vivo system for testing new therapeutic approaches to treat and manage SAA. Activation of self-reactive T cells in human AA and alloreactive donor T cells in mouse AA models involves interaction of T cells with dendritic cells (DCs) as professional APCs. DCs express β2 integrin CD11b/CD18 (Mac-1), which plays an important role in inflammation, cell-mediated killing and cell activation. Notably, Mac-1 expressed on DCs is inactive and is not activated on contact with T cells. More importantly, activation of Mac-1 on DCs by Mg2+ treatment significantly reduces their T cell-activating capacity, and active CD11b represses DC cross-priming of cytotoxic T cells. Thus, activation of Mac-1 on DCs represents a potential new immunosuppressive strategy for reducing pathological T cell responses in AA. Dr. Gupta has identified novel Mac-1 agonists, termed Leukadherins (LAs1-3) that bind to and activate Mac-1. Multiple lines of experimental evidence generated by Dr. Gupta’s and Dr. Jurecic’s groups have shown that LAs have potent anti-inflammatory and immunosuppressive properties. For example, treatment with LA1 is safely and effectively reducing the onset and severity of Experimental Autoimmune Encephalomyelitis (EAE) in mice, induced by Myelin Oligodendrocyte Glycoprotein (MOG). Moreover, in EAE mice LA1 efficiently decreased the activation of myelin-reactive T cells and their IFN-γ production. We hypothesized that by activating Mac-1 on DCs LAs could effectively (a) reduce T cell-activating capacity of DCs and attenuate allo-reactive T cell responses, and (b) reduce severity of AA in mouse models. Indeed, in mixed lymphocyte reaction, which depends on stimulation of allogeneic T cells by DCs, LA1 significantly suppressed proliferation of lymph node T cells from C57BL6/J mice in the presence of irradiated splenocytes from allogeneic DBA/2J mice. SAA was induced in B6D2F1 mice by tail vein injection of 5 x 10e7 LNCs from C57BL/6J mice. The untreated AA mice died within 21 days of LNC infusion and exhibited (a) severe BM aplasia, (b) ~5-fold expansion of CD4+ T cells and >20-fold expansion of CD8+ T cells in comparison to Control B6D2F1 mice, and (c) severe depletion of HSCs (LSK CD150+ CD48- BM cells); Multipotent progenitors (MPPs, LSK CD150- CD48- BM cells); and Hematopoietic progenitors (HPC-1, LSK CD150- CD48+ cells; HPC-2, LSK CD150+ CD48+ cells). In contrast, AA mice treated IP with 1 mg/kg/day of LA1 for 7 or 21 days after LNC infusion exhibited (a) mild BM aplasia and improved BM cellularity, (b) significantly reduced expansion of CD4 (~2-fold) and CD8 (~12-fold) T cells in the BM, and (c) significantly improved frequency and total numbers of HSCs and progenitors in comparison to untreated AA mice. More importantly, treatment of AA mice with LA1 for 21 days resulted in 40-50% of AA mice surviving for more than 7 weeks after LNC infusion. These results demonstrate that treatment with LA1 can safely convert SAA into a moderate disease in preclinical mouse AA models and provide a platform for testing of LAs as new alternative or adjuvant therapy to manage ongoing AA in patients who (1) are not responding to IST and are not candidates for BMT, and/or (2) are undergoing IST and awaiting BMT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mast Cells Modulate Antigen-Specific CD8+ T Cell Activation During LCMV Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Yana Hackler ◽  
Frank Siebenhaar ◽  
Max Löhning ◽  
Marcus Maurer ◽  
Melba Muñoz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mast Cells ◽  
Immune Responses ◽  
Cytokine Production ◽  
T Cell Responses ◽  
Type I ◽  
Cell Responses ◽  
Deficient Mice ◽  
Lcmv Infection

Mast cells (MCs), strategically localized at mucosal surfaces, provide first-line defense against pathogens and shape innate and adaptive immune responses. Recent studies have shown that MCs are involved in pathogenic responses to several viruses including herpes simplex viruses, dengue virus, vaccinia virus and influenza virus. However, the underlying mechanisms of MCs in the activation of CD8+ T cells during viral infections are not fully understood. Therefore, we investigate the role of MCs in the development of virus-specific CD8+ T cell responses using the well-characterized murine lymphocytic choriomeningitis virus (LCMV) model and the transgenic MasTRECK mice that contain the human diphtheria toxin receptor as an inducible MC-deficient model. Here, we report that MCs are essential for the activation and expansion of virus-specific CD8+ T cells. After MC depletion and subsequent intradermal LCMV infection, the CD8+ T cell effector phenotype and antiviral cytokine production were impaired at the peak of infection (day 8 p.i.). Importantly, MC-deficient mice were unable to control the infection and exhibited significantly higher viral loads in the spleen and in the ear draining lymph nodes compared to that of wild type control mice. In the absence of MCs, dendritic cell (DC) activation was impaired upon LCMV infection. In addition, type-I interferon (IFN) levels in the serum and in the spleen of MC-deficient mice were reduced during the first days of infection. Interestingly, depletion of MCs after intradermal LCMV infection did not impair virus-specific CD8+ T cell expansion, activation or antiviral cytokine production. In summary, our results indicate that MCs play a pivotal role in the activation and antiviral functions of CD8+ T cells through proper DC activation. A better understanding of the impact of MCs on CD8+ T cell responses is mandatory to improve antiviral immune responses.

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