Shaping Adaptive Immune Responses Research Articles

The role of the cGAS-STING signaling pathway in viral infections, inflammatory and autoimmune diseases.

Pattern recognition receptors are an essential part of the immune system, which detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and help shape both innate and adaptive immune responses. When dsDNA is present, cyclic GMP-AMP Synthase (cGAS) produces a second messenger called cyclic GMP-AMP (cGAMP), which then triggers an adaptor protein called STING, and eventually activates the expression of type I interferon (IFN) and pro-inflammatory cytokines in immune cells. The cGAS-STING signaling pathway has been receiving a lot of attention lately as a key immune-surveillance mediator. In this review, we summarize the present circumstances of the cGAS-STING signaling pathway in viral infections and inflammatory diseases, as well as autoimmune diseases. Modulation of the cGAS-STING signaling pathway provides potential strategies for treating viral infections, inflammatory diseases, and autoimmune diseases.

Sphingolipid biosynthesis is essential for metabolic rewiring during TH17 cell differentiation.

T helper 17 (TH17) cells are implicated in autoimmune diseases, and several metabolic processes are shown to be important for their development and function. In this study, we report an essential role for sphingolipids synthesized through the de novo pathway in TH17 cell development. Deficiency of SPTLC1, a major subunit of serine palmitoyl transferase enzyme complex that catalyzes the first and rate-limiting step of de novo sphingolipid synthesis, impaired glycolysis in differentiating TH17 cells by increasing intracellular reactive oxygen species (ROS) through enhancement of nicotinamide adenine dinucleotide phosphate oxidase 2 activity. Increased ROS leads to impaired activation of mammalian target of rapamycin C1 and reduced expression of hypoxia-inducible factor 1-alpha and c-Myc-induced glycolytic genes. SPTLCI deficiency protected mice from developing experimental autoimmune encephalomyelitis and experimental T cell transfer colitis. Our results thus show a critical role for de novo sphingolipid biosynthetic pathway in shaping adaptive immune responses with implications in autoimmune diseases.

Unraveling the Role of Epithelial Cells in the Development of Chronic Rhinosinusitis.

The pathophysiology of CRS is multifactorial and complex yet needs to be completed. Recent evidence emphasizes the crucial part played by epithelial cells in the development of CRS. The epithelial cells act as physical barriers and play crucial roles in host defense, including initiating and shaping innate and adaptive immune responses. This review aims to present a comprehensive understanding of the significance of nasal epithelial cells in CRS. New research suggests that epithelial dysfunction plays a role in developing CRS through multiple mechanisms. This refers to issues with a weakened barrier function, disrupted mucociliary clearance, and irregular immune responses. When the epithelial barrier is compromised, it can lead to the passage of pathogens and allergens, triggering inflammation in the body. Furthermore, impaired mucociliary clearance can accumulate pathogens and secretions of inflammatory mediators, promoting chronic inflammation. Epithelial cells can release cytokines and chemokines, which attract and activate immune cells. This can result in an imbalanced immune response that continues to cause inflammation. The interaction between nasal epithelial cells and various immune cells leads to the production of cytokines and chemokines, which can either increase or decrease inflammation. By comprehending the role of epithelial cells in CRS, we can enhance our understanding of the disease's pathogenesis and explore new therapeutics.

Structural basis of CXC chemokine receptor 1 ligand binding and activation

Neutrophil granulocytes play key roles in innate immunity and shaping adaptive immune responses. They are attracted by chemokines to sites of infection and tissue damage, where they kill and phagocytose bacteria. The chemokine CXCL8 (also known as interleukin-8, abbreviated IL-8) and its G-protein-coupled receptors CXCR1 and CXCR2 are crucial elements in this process, and also the development of many cancers. These GPCRs have therefore been the target of many drug development campaigns and structural studies. Here, we solve the structure of CXCR1 complexed with CXCL8 and cognate G-proteins using cryo-EM, showing the detailed interactions between the receptor, the chemokine and Gαi protein. Unlike the closely related CXCR2, CXCR1 strongly prefers to bind CXCL8 in its monomeric form. The model shows that steric clashes would form between dimeric CXCL8 and extracellular loop 2 (ECL2) of CXCR1. Consistently, transplanting ECL2 of CXCR2 onto CXCR1 abolishes the selectivity for the monomeric chemokine. Our model and functional analysis of various CXCR1 mutants will assist efforts in structure-based drug design targeting specific CXC chemokine receptor subtypes.

Toll-like Receptor Response to Human Immunodeficiency Virus Type 1 or Co-Infection with Hepatitis B or C Virus: An Overview.

Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors that play important roles in the early detection of pathogen-associated molecular patterns and shaping innate and adaptive immune responses, which may influence the consequences of infection. Similarly to other viral infections, human immunodeficiency virus type 1 (HIV-1) also modulates the host TLR response; therefore, a proper understanding of the response induced by human HIV-1 or co-infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), due to the common mode of transmission of these viruses, is essential for understanding HIV-1 pathogenesis during mono- or co-infection with HBV or HCV, as well as for HIV-1 cure strategies. In this review, we discuss the host TLR response during HIV-1 infection and the innate immune evasion mechanisms adopted by HIV-1 for infection establishment. We also examine changes in the host TLR response during HIV-1 co-infection with HBV or HCV; however, this type of study is extremely scarce. Moreover, we discuss studies investigating TLR agonists as latency-reverting agents and immune stimulators towards new strategies for curing HIV. This understanding will help develop a new strategy for curing HIV-1 mono-infection or co-infection with HBV or HCV.

Cell entry and innate sensing shape adaptive immune responses to adenovirus-based vaccines.

Nonreplicating adenovirus-based vectors have been successfully implemented as prophylactic vaccines against infectious viral diseases and induce protective cellular and humoral responses. Differences in the mechanisms of cellular entry or endosomal escape of these vectors contribute to differences in innate immune sensing between adenovirus species. Innate immune responses to adenovirus-based vaccines, such as interferon signaling, have been reported to affect the development of adaptive responses in preclinical studies, although limited data are available in humans. Understanding the mechanisms of these early events is critical for the development of vaccines that elicit effective and durable adaptive immune responses while maintaining an acceptable reactogenicity profile.

Epigenetics: An opportunity to shape innate and adaptive immune responses.

Epigenetics connects genetic and environmental factors: it includes DNA methylation, histone post-translational modifications and the regulation of chromatin accessibility by non-coding RNAs, all of which control constitutive or inducible gene transcription. This plays a key role in harnessing the transcriptional programs of both innate and adaptive immune cells due to its plasticity and environmental-driven nature, piloting myeloid and lymphoid cell fate decisions with no change in their genomic sequence. In particular, epigenetic marks at the site of lineage-specific transcription factors and maintenance of cell type-specific epigenetic modifications, referred to as 'epigenetic memory', dictate cell differentiation, cytokine production and functional capacity following repeated antigenic exposure in memory T cells. Moreover, metabolic and epigenetic reprogramming occurring during a primary innate immune response leads to enhanced responses to secondary challenges, a phenomenon known as 'trained immunity'. Here, we discuss how stable and dynamic epigenetic states control immune cell identity and plasticity in physiological and pathological conditions. Dissecting the regulatory circuits of cell fate determination and maintenance is of paramount importance for understanding the delicate balance between immune cell activation and tolerance, in healthy conditions and in autoimmune diseases.

Defying convention in the time of COVID-19: Insights into the role of γδ T cells.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is a complex disease which immune response can be more or less potent. In severe cases, patients might experience a cytokine storm that compromises their vital functions and impedes clearance of the infection. Gamma delta (γδ) T lymphocytes have a critical role initiating innate immunity and shaping adaptive immune responses, and they are recognized for their contribution to tumor surveillance, fighting infectious diseases, and autoimmunity. γδ T cells exist as both circulating T lymphocytes and as resident cells in different mucosal tissues, including the lungs and their critical role in other respiratory viral infections has been demonstrated. In the context of SARS-CoV-2 infection, γδ T cell responses are understudied. This review summarizes the findings on the antiviral role of γδ T cells in COVID-19, providing insight into how they may contribute to the control of infection in the mild/moderate clinical outcome.

Class I PI3K regulatory subunits control differentiation of dendritic cell subsets and regulate Flt3L mediated signal transduction

Dendritic cells (DCs) play pivotal roles in initiating and shaping both innate and adaptive immune responses. The spatiotemporal expression of transcription factor networks and activation of specific signal transduction pathways determine the specification, distribution and differentiation of DC subsets. Even though pioneering studies have established indispensable roles for specific catalytic subunits (p110δ and p110γ) in immune cells, functions of the regulatory subunits, particularly of Class I PI3K, within the hematopoietic system remain incompletely understood. In the study presented here, we deleted the key regulatory subunits—p85α and p85β of the Class IA PI3K in hematopoietic cells and studied its impact on DC differentiation. Our studies identify that a deficiency of p85 causes increased differentiation of conventional DC (cDC) 2 and plasmacytoid DC (pDC) subsets in the spleen. On the other hand, DC numbers in the bone marrow (BM), thymus and lymph nodes were decreased in p85 mutant mice. Analysis of DC-specific progenitors and precursors indicated increased numbers in the BM and spleen of p85 deficient mice. In-vitro differentiation studies demonstrated augmented DC-differentiation capacities of p85 deficient BM cells in the presence of GM-CSF and Flt3L. BM chimera studies established that p85 deficiency affects DC development through cell intrinsic mechanisms. Molecular studies revealed increased proliferation of DCs and common DC progenitors (CDPs) in the absence of p85 and altered signal transduction pathways in p85 mutant DC subsets in response to Flt3L. In essence, data presented here, for the first time, unequivocally establish that the P85α subunit of class IA PI3Ks has an indispensable role in the development and maintenance of DCs.

Abstract 4261: CD27 a new immuno-oncology target shaping innate and adaptive anti-tumor immune responses

Abstract CD27 is a member of the TNF-receptor superfamily, highly expressed on CD4+ and CD8+ T cells as well as on NK and NKT cells. It plays a key role on T cell proliferation and differentiation after stimulation with its ligand CD70. The co-stimulatory signal of CD27 on T cell is mediated via the NFκB pathway but also via the phosphatidylinositol 3 kinase and the protein kinase B. CD27/CD70 co-stimulation has the potential to boost immunity by T-cell activation, clonal expansion and enhanced differentiation into antigen specific cytotoxic and memory T cells. CD27/CD70 also influences the innate immune response via a direct activation of the NK cells and a subsequent secretion of interferon-gamma (IFN-γ). Therefore, CD27 signaling promotes cytotoxic T cell based anti-tumor immunity. With its central role in an immunological response, CD27 is a promising target for antitumor therapy. Previous works have demonstrated the efficacy of an agonistic CD27 antibody in controlling tumor growth and metastasis in different mice models including melanoma, renal cell carcinoma, breast cancer and lymphomas. This anti-tumor effect is mediated in part by an effective recruitment of IFN-γ producing CD8+ T cells within the tumor. Moreover, CD27 stimulation of Tumor Infiltrating Lymphocytes (TILs) can lower their threshold of activation and provide a broader repertoire of Ag-reactive T cells within the tumor. We have selected a lead therapeutic antibody from our library of 147 fully human anti-CD27 monoclonal antibodies generated in the Trianni mice. After confirming its binding potency and selectivity as well as its cross-reactivity with Non-Human Primate (NHP)-CD27 but not with the mouse-CD27, this lead candidate demonstrated strong agonistic proprieties. This was shown by its ability to induce a strong NFκB signal as well as to induce T cell proliferation and activation with secretion of pro-inflammatory cytokines. This antibody demonstrated agonistic proprieties without cross-linking confirming its potency. T cell activation observed after treatment with our anti-CD27 antibody only occurs in the presence of TCR engagement, preventing the risk of spontaneous activation of naïve T cells in vivo. The ability of our CD27 monoclonal antibody to increase an immune response was confirmed in a Mixed Lymphocyte Reaction assay with multiple donors. The role played by the NK cells and their activation via CD27 antibody was also demonstrated. To evaluate the anti-tumor functions of our lead antibody as a single agent or in combination with other immuno-therapies in vivo we have used human CD27 transgenic mice. We have demonstrated in the MB49 bladder tumor model as well as the EG7 thymoma model that our lead antibody induces a strong single agent anti-tumor activity and these tumors were totally controlled in combination with an anti-PD1 antibody. We are now analyzing the pharmacokinetic and pharmacodynamic of our antibody as well as its safety in a NHP model Citation Format: Thierry Guillaudeux, Yulia Ovechkina, Shaarwari Sridhar, David Peckham, Jessica Cross, Nathan Eyde, Emily Frazier, Neda Kabi, Remington Lance, Kurt Lustig, Mei Xu, Tarcha Eric, Shawn Iadonato. CD27 a new immuno-oncology target shaping innate and adaptive anti-tumor immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4261.

Sex, Age, and Ethnic Background Shape Adaptive Immune Responses Induced by the SARS-CoV-2 mRNA Vaccine.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine-induced adaptive responses have been well investigated. However, the effects of sex, age, and ethnic background on the immune responses elicited by the mRNA vaccine remain unclear. Here, we performed comprehensive analyses of adaptive immune responses elicited by the SARS-CoV-2 mRNA vaccine. Vaccine-induced antibody and T cell responses declined over time but persisted after 3 months, and switched memory B cells were even increased. Spike-specific CD4+ T and CD8+ T cell responses were decreased against the B.1.351 variant, but not against B.1.1.7. Interestingly, T cell reactivity against B.1.617.1 and B.1.617.2 variants was decreased in individuals carrying HLA-A24, suggesting adaptive immune responses against variants are influenced by different HLA haplotypes. T follicular helper cell responses declined with increasing age in both sexes, but age-related decreases in antibody levels were observed only in males, and this was associated with the decline of T peripheral helper cell responses. In contrast, vaccine-induced CD8+ T cell responses were enhanced in older males. Taken together, these findings highlight that significant differences in the reactogenicity of the adaptive immune system elicited by mRNA vaccine were related to factors including sex, age, and ethnic background.

A Combination Adjuvant for the Induction of Potent Antiviral Immune Responses for a Recombinant SARS-CoV-2 Protein Vaccine.

Several SARS-CoV-2 vaccines have received EUAs, but many issues remain unresolved, including duration of conferred immunity and breadth of cross-protection. Adjuvants that enhance and shape adaptive immune responses that confer broad protection against SARS-CoV-2 variants will be pivotal for long-term protection as drift variants continue to emerge. We developed an intranasal, rationally designed adjuvant integrating a nanoemulsion (NE) that activates TLRs and NLRP3 with an RNA agonist of RIG-I (IVT DI). The combination adjuvant with spike protein antigen elicited robust responses to SARS-CoV-2 in mice, with markedly enhanced TH1-biased cellular responses and high virus-neutralizing antibody titers towards both homologous SARS-CoV-2 and a variant harboring the N501Y mutation shared by B1.1.7, B.1.351 and P.1 variants. Furthermore, passive transfer of vaccination-induced antibodies protected naive mice against heterologous viral challenge. NE/IVT DI enables mucosal vaccination, and has the potential to improve the immune profile of a variety of SARS-CoV-2 vaccine candidates to provide effective cross-protection against future drift variants.

Mast Cells Modulate Antigen-Specific CD8+ T Cell Activation During 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.

β2 Integrin Regulation of Neutrophil Functional Plasticity and Fate in the Resolution of Inflammation.

Neutrophils act as the first line of cellular defense against invading pathogens or tissue injury. Their rapid recruitment into inflamed tissues is critical for the elimination of invading microorganisms and tissue repair, but is also capable of inflicting damage to neighboring tissues. The β2 integrins and Mac-1 (CD11b/CD18, αMβ2 or complement receptor 3) in particular, are best known for mediating neutrophil adhesion and transmigration across the endothelium and phagocytosis of microbes. However, Mac-1 has a broad ligand recognition property that contributes to the functional versatility of the neutrophil population far beyond their antimicrobial function. Accumulating evidence over the past decade has demonstrated roles for Mac-1 ligands in regulating reverse neutrophil transmigration, lifespan, phagocytosis-induced cell death, release of neutrophil extracellular traps and efferocytosis, hence extending the traditional β2 integrin repertoire in shaping innate and adaptive immune responses. Understanding the functions of β2 integrins may partly explain neutrophil heterogeneity and may be instrumental to develop novel therapies specifically targeting Mac-1-mediated pro-resolution actions without compromising immunity. Thus, this review details novel insights on outside-in signaling through β2 integrins and neutrophil functional heterogeneity pertinent to the resolution of inflammation.

IL-12 Family Cytokines in Cancer and Immunotherapy.

Simple SummaryThe IL-12 family cytokines play an important role in regulating the tumor immune contexture. Recent efforts geared towards the development of better immune therapeutic approaches have identified the need to overcome immune suppression and improve the quantity and quality of anti-tumor effector immune cells within the tumor milieu. In this review, we summarize the recent findings on IL-12 family cytokines in regulating anti-tumor immunity as well as the effectiveness and benefits of enhancing anti-tumor immunity in pre-clinical and clinical settings by targeting IL-12 family cytokines.The IL-12 family cytokines are a group of unique heterodimeric cytokines that include IL-12, IL-23, IL-27, IL-35 and, most recently, IL-39. Recent studies have solidified the importance of IL-12 cytokines in shaping innate and adaptive immune responses in cancer and identified multipronged roles for distinct IL-12 family members, ranging from effector to regulatory immune functions. These cytokines could serve as promising candidates for the development of immunomodulatory therapeutic approaches. Overall, IL-12 can be considered an effector cytokine and has been found to engage anti-tumor immunity by activating the effector Th1 response, which is required for the activation of cytotoxic T and NK cells and tumor clearance. IL-23 and IL-27 play dual roles in tumor immunity, as they can both activate effector immune responses and promote tumor growth by favoring immune suppression. IL-35 is a potent regulatory cytokine and plays a largely pro-tumorigenic role by inhibiting effector T cells. In this review, we summarize the recent findings on IL-12 family cytokines in the control of tumor growth with an emphasis primarily on immune regulation. We underscore the clinical implications for the use of these cytokines either in the setting of monotherapy or in combination with other conventional therapies for the more effective treatment of malignancies.

Modulating the Tumour Microenvironment by Intratumoural Injection of Pattern Recognition Receptor Agonists.

Simple SummaryThe immune system is capable of eliminating solid cancers through the action of immune cells that recognise antigens that are unique to tumour tissue. However, the activity of tumour-specific immune cells is often blunted by the immunosuppressive environment within the tumour core. One strategy to overcome this limitation is to inject immune modulators directly into the tumour bed to stimulate the local network of immune cells. Not only does this promote local antitumour activity, but also facilitates the infiltration of immune cells with antitumour activity at distant tumour sites. A major class of compounds used for this purpose are recognised by pattern recognition receptors (PRR), providing molecular cues typically associated with infection or tissue damage to inflate the response. In this review, we summarise research into the use of such compounds in preclinical studies, including promising studies conducted in combination with conventional cancer therapies and other immunotherapies. Signalling through pattern recognition receptors (PRRs) leads to strong proinflammatory responses, enhancing the activity of antigen presenting cells and shaping adaptive immune responses against tumour associated antigens. Unfortunately, toxicities associated with systemic administration of these agonists have limited their clinical use to date. Direct injection of PRR agonists into the tumour can enhance immune responses by directly modulating the cells present in the tumour microenvironment. This can improve local antitumour activity, but importantly, also facilitates systemic responses that limit tumour growth at distant sites. As such, this form of therapy could be used clinically where metastatic tumour lesions are accessible, or as neoadjuvant therapy. In this review, we summarise current preclinical data on intratumoural administration of PRR agonists, including new strategies to optimise delivery and impact, and combination studies with current and promising new cancer therapies.

Leishmania regulates host macrophage miRNAs expression by engaging transcription factor c-Myc.

Parasites of Leishmania genus have developed sophisticated strategies allowing them to deactivate their host macrophage to promote their survival. It has become clear that miRNAs play important roles in shaping innate and adaptive immune responses toward pathogens. It is not surprising that several pathogens including Leishmania have evolved the ability to regulate host macrophage miRNA expression in order to manipulate host cell phenotypes to their advantage. However, very little is known about the mechanisms used by intracellular pathogens to drive changes in host cell miRNA abundance. In this review, Leishmania exploitation of macrophage transcription factor c-Myc as a critical proxy virulence factor to regulate abundance of macrophage miRNAs influencing macrophage physiology to promote its survival will be discussed.

Glufosinate constrains synchronous and metachronous metastasis by promoting anti-tumor macrophages.

Glutamine synthetase (GS) generates glutamine from glutamate and controls the release of inflammatory mediators. In macrophages, GS activity, driven by IL10, associates to the acquisition of M2‐like functions. Conditional deletion of GS in macrophages inhibits metastasis by boosting the formation of anti‐tumor, M1‐like, tumor‐associated macrophages (TAMs). From this basis, we evaluated the pharmacological potential of GS inhibitors in targeting metastasis, identifying glufosinate as a specific human GS inhibitor. Glufosinate was tested in both cultured macrophages and on mice bearing metastatic lung, skin and breast cancer. We found that glufosinate rewires macrophages toward an M1‐like phenotype both at the primary tumor and metastatic site, countering immunosuppression and promoting vessel sprouting. This was also accompanied to a reduction in cancer cell intravasation and extravasation, leading to synchronous and metachronous metastasis growth inhibition, but no effects on primary tumor growth. Glufosinate treatment was well‐tolerated, without liver and brain toxicity, nor hematopoietic defects. These results identify GS as a druggable enzyme to rewire macrophage functions and highlight the potential of targeting metabolic checkpoints in macrophages to treat cancer metastasis.

In vivo tracking: Using a photoconvertible system to probe immune cell entry and exit in the context of inflammation

Abstract Chronic inflammatory diseases such as Crohn’s disease and rheumatoid arthritis affect millions of people worldwide. During an inflammatory response, immune cells enter the inflamed tissue to mediate pathogen clearance, however, their activation and overaccumulation in the tissue can lead to chronic inflammation and autoimmunity. Little is known about the signals that regulate immune cell entry into and exit from these inflamed tissues or about the retention cues that play a role in their accumulation. Therefore, a better understanding of these signals would inform the design of therapeutics intended to alleviate chronic inflammation. To study immune cell movement between a site of inflammation and lymphoid organs, our lab has acquired a mouse model that allows for the in vivo labeling of a subset of cells in time and space. The cells of Kaede transgenic mice constitutively express the photoconvertible fluorescent Kaede protein. CFA/OVA-inflamed ears were photoconverted from Kaede green to red by violet light exposure and the trafficking of Kaede red cells out of the skin to the draining lymph node was assessed over the course of 24 hours. Based on preliminary data, we found that, of the subsets assessed, neutrophils and CD4+ T cells made up the largest percentages of immune cells exiting the inflamed tissue on day 5 of inflammation. On the other hand, far fewer conventional dendritic cells and macrophages were seen to enter the draining lymph node from the inflamed tissue. The role of these tissue-emigrant immune cells is not yet clear, but cells such as neutrophils may play a role in shaping adaptive immune responses in the draining lymph node.

Febrile Temperature Critically Controls the Differentiation and Pathogenicity of T Helper 17 Cells

Fever, an evolutionarily conserved physiological response to infection, is also commonly associated with many autoimmune diseases, but its role in Tcell differentiation and autoimmunity remains largely unclear. T helper 17 (Th17) cells are critical in host defense and autoinflammatory diseases, with distinct phenotypes and pathogenicity. Here, we show that febrile temperature selectively regulated Th17 cell differentiation invitro in enhancing interleukin-17 (IL-17), IL-17F, and IL-22 expression. Th17 cells generated under febrile temperature (38.5°C-39.5°C), compared with those under 37°C, showed enhanced pathogenic gene expression with increased pro-inflammatory activities invivo. Mechanistically, febrile temperature promoted SUMOylation of SMAD4 transcription factor to facilitate its nuclear localization; SMAD4 deficiency selectively abrogated the effects of febrile temperature on Th17 cell differentiation both invitro and ameliorated an autoimmune disease model. Our results thus demonstrate a critical role of fever in shaping adaptive immune responses with implications in autoimmune diseases.