RESUMO
The molecular mechanisms leading to the establishment of immunological memory are inadequately understood, limiting the development of effective vaccines and durable antitumor immune therapies. Here, we show that ectopic OCA-B expression is sufficient to improve antiviral memory recall responses, while having minimal effects on primary effector responses. At peak viral response, short-lived effector T cell populations are expanded but show increased Gadd45b and Socs2 expression, while memory precursor effector cells show increased expression of Bcl2, Il7r, and Tcf7 on a per-cell basis. Using an OCA-B mCherry reporter mouse line, we observe high OCA-B expression in CD4+ central memory T cells. We show that early in viral infection, endogenously elevated OCA-B expression prospectively identifies memory precursor cells with increased survival capability and memory recall potential. Cumulatively, the results demonstrate that OCA-B is both necessary and sufficient to promote CD4 T cell memory in vivo and can be used to prospectively identify memory precursor cells.
Assuntos
Linfócitos T CD4-Positivos , Células T de Memória , Animais , Camundongos , Memória Imunológica , Memória , Receptores de Interleucina-7 , Transativadores , Proteínas GADD45 , Antígenos de DiferenciaçãoRESUMO
Following viral infection, CD4+ T cell differentiation is tightly regulated by cytokines and TCR signals. Although most activated CD4+ T cells express IL-2Rα after lymphocytic choriomeningtis virus infection, by day 3 postinfection, only half of activated T cells maintain expression. IL-2Rα at this time point distinguishes precursors for terminally differentiated Th1 cells (IL-2Rαhi) from precursors for Tfh cells and memory T cells (IL-2Rαlo) and is linked to strong TCR signals. In this study, we test whether TCR-dependent IL-2 links the TCR to CD4+ T cell differentiation. We employ a mixture of anti-IL-2 Abs to neutralize IL-2 throughout the primary CD4+ T cell response to lymphocytic choriomeningitis virus infection in mice or only after the establishment of lineage-committed effector cells (day 3 postinfection). We report that IL-2 signals drive the formation of Th1 precursor cells in the early stages of the immune response and sustain Th1 responses during its later stages (after day 3). Effector-stage IL-2 also shapes the composition and function of resulting CD4+ memory T cells. Although IL-2 has been shown previously to drive Th1 differentiation by reducing the activity of the transcriptional repressor TCF-1, we found that sustained IL-2 signals were still required to drive optimal Th1 differentiation even in the absence of TCF-1. Therefore, we concluded that IL-2 plays a central role throughout the effector phase in regulating the balance between Th1 and Tfh effector and memory cells via mechanisms that are both dependent and independent of its role in modulating TCF-1 activity.
Assuntos
Interleucina-2 , Células Th1 , Animais , Camundongos , Linfócitos T CD4-Positivos , Diferenciação Celular , Memória Imunológica , Subunidade alfa de Receptor de Interleucina-2 , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos TRESUMO
Chronic inflammation is a contributing factor to most life-shortening human diseases. However, the molecular and cellular mechanisms that sustain chronic inflammatory responses remain poorly understood, making it difficult to treat this deleterious condition. Using a mouse model of age-dependent inflammation that results from a deficiency in miR-146a, we demonstrate that miR-155 contributed to the progressive inflammatory disease that emerged as Mir146a(-/-) mice grew older. Upon analyzing lymphocytes from inflamed versus healthy middle-aged mice, we found elevated numbers of T follicular helper (Tfh) cells, germinal center (GC) B cells, and autoantibodies, all occurring in a miR-155-dependent manner. Further, Cd4-cre Mir155(fl/fl) mice were generated and demonstrated that miR-155 functions in T cells, in addition to its established role in B cells, to promote humoral immunity in a variety of contexts. Taken together, our study discovers that miR-146a and miR-155 counterregulate Tfh cell development that drives aberrant GC reactions during chronic inflammation.
Assuntos
Centro Germinativo/imunologia , Inflamação/imunologia , MicroRNAs/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Transferência Adotiva , Animais , Autoanticorpos/biossíntese , Autoanticorpos/imunologia , Linfócitos B/imunologia , Antígenos CD4/biossíntese , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Antígeno 2 Relacionado a Fos/genética , Centro Germinativo/citologia , Imunidade Humoral , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Interferência de RNA , RNA Interferente PequenoRESUMO
In this issue of Immunity, Olson et al. (2013) demonstrate that circulating CD8⺠memory T cells with an effector-like phenotype, previously thought to be mostly senescent, provide robust protection from a secondary pathogen challenge despite their poor secondary proliferative response.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Infecções por Poxviridae/imunologia , Subpopulações de Linfócitos T/imunologia , Vaccinia virus/imunologia , Animais , FemininoRESUMO
During CD4⺠T cell activation, T cell receptor (TCR) signals impact T cell fate, including recruitment, expansion, differentiation, trafficking, and survival. To determine the impact of TCR signals on the fate decision of activated CD4⺠T cells to become end-stage effector or long-lived memory T helper 1 (Th1) cells, we devised a deep-sequencing-based approach that allowed us to track the evolution of TCR repertoires after acute infection. The transition of effector Th1 cells into the memory pool was associated with a significant decrease in repertoire diversity, and the major histocompatibility complex (MHC) class II tetramer off rate, but not tetramer avidity, was a key predictive factor in the representation of individual clonal T cell populations at the memory stage. We conclude that stable and sustained interactions with antigens during the development of Th1 responses to acute infection are a determinative factor in promoting the differentiation of Th1 memory cells.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Memória Imunológica , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/imunologia , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de SinaisRESUMO
T cell responses are essential for appropriate protection against pathogens. T cell immunity is achieved through the ability to discriminate between foreign and self-molecules, and this relies heavily on stringent T cell receptor (TCR) specificity. Recently, bystander activated T lymphocytes, that are specific for unrelated epitopes during an antigen-specific response, have been implicated in diverse diseases. Numerous infection models have challenged the classic dogma of T cell activation as being solely dependent on TCR and major histocompatibility complex (MHC) interactions, indicating an unappreciated role for pathogen-associated receptors on T cells. We discuss here the specific roles of bystander activated T cells in pathogenesis, shedding light on the ability of these cells to modulate disease severity independently from TCR recognition.
Assuntos
Comunicação Celular , Linfócitos T/citologia , Linfócitos T/imunologia , Animais , Humanos , Complexo Principal de Histocompatibilidade/imunologia , Receptores de Antígenos de Linfócitos T/imunologiaRESUMO
Macroscopic anatomy has traditionally been taught using cadaveric material, lectures and a variable amount of additional resources such as online modules. Anatomical models have also been used to assist in teaching. Of these, traditional plastic models have been shown to be effective educational tools, yet have significant drawbacks such as a lack of anatomical detail and texturisation. Three-dimensional (3D) printed models stand to solve these problems and widen access to high-quality anatomical teaching. This paper outlines the use of 3D multi-planar imaging (CT and MRI) as a framework to develop an accurate model of the retroperitoneum. CT and MRI scans were used to construct a virtual 3D model of the retroperitoneum. This was printed locally as a full-size colour model for use in medical education. We give a complete account of the processes and software used. This study is amongst the first of a series in which we will document the newly formed Oxford Library of Anatomy. This series will provide the methodology for the production of models from CT and MRI scans, and the Oxford Library of Anatomy will provide a complete series of some of the most complex anatomical areas and ones which degrade quickly when a real cadaver is being used. In our own internal experience, the models are highly accurate, reproducible and durable, as compared to prosected specimens. We hope they will form an important adjunct in the teaching of the subject.
Assuntos
Abdome/anatomia & histologia , Imageamento Tridimensional/métodos , Região Lombossacral/anatomia & histologia , Modelos Anatômicos , Pelve/anatomia & histologia , Abdome/diagnóstico por imagem , Educação de Graduação em Medicina , Humanos , Região Lombossacral/diagnóstico por imagem , Imageamento por Ressonância Magnética , Pelve/diagnóstico por imagem , Impressão Tridimensional , Tomografia Computadorizada por Raios XRESUMO
T cells predominate the immune responses in the synovial fluid of patients with persistent Lyme arthritis; however, their role in Lyme disease remains poorly defined. Using a murine model of persistent Lyme arthritis, we observed that bystander activation of CD4+ and CD8+ T cells leads to arthritis-promoting IFN-γ, similar to the inflammatory environment seen in the synovial tissue of patients with posttreatment Lyme disease. TCR transgenic mice containing monoclonal specificity toward non-Borrelia epitopes confirmed that bystander T cell activation was responsible for disease development. The microbial pattern recognition receptor TLR2 was upregulated on T cells following infection, implicating it as marker of bystander T cell activation. In fact, T cell-intrinsic expression of TLR2 contributed to IFN-γ production and arthritis, providing a mechanism for microbial-induced bystander T cell activation during infection. The IL-10-deficient mouse reveals a novel TLR2-intrinsic role for T cells in Lyme arthritis, with potentially broad application to immune pathogenesis.
Assuntos
Interleucina-10/deficiência , Doença de Lyme/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Receptor 2 Toll-Like/imunologia , Animais , Feminino , Interleucina-10/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
In this issue of Immunity, Baaten et al. (2010) describe a previously unknown role for CD44 in counteracting Fas-mediated apoptosis of Th1 effector cells during clonal expansion and allowing their entry into the memory pool.
Assuntos
Memória Imunológica/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Animais , HumanosRESUMO
MicroRNA-155 (miR-155) regulates antitumor immune responses. However, its specific functions within distinct immune cell types have not been delineated in conditional KO mouse models. In this study, we investigated the role of miR-155 specifically within T cells during the immune response to syngeneic tumors. We found that miR-155 expression within T cells is required to limit syngeneic tumor growth and promote IFNγ production by T cells within the tumor microenvironment. Consequently, we found that miR-155 expression by T cells is necessary for proper tumor-associated macrophage expression of IFNγ-inducible genes. We also found that immune checkpoint-blocking (ICB) antibodies against programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) restored antitumor immunity in miR-155 T cell-conditional KO mice. We noted that these ICB antibodies rescued the levels of IFNγ-expressing T cells, expression of multiple activation and effector genes expressed by tumor-infiltrating CD8+ and CD4+ T cells, and tumor-associated macrophage activation. Moreover, the ICB approach partially restored expression of several derepressed miR-155 targets in tumor-infiltrating, miR-155-deficient CD8+ T cells, suggesting that miR-155 and ICB regulate overlapping pathways to promote antitumor immunity. Taken together, our findings highlight the multifaceted role of miR-155 in T cells, in which it promotes antitumor immunity. These results suggest that the augmentation of miR-155 expression could be used to improve anticancer immunotherapies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Melanoma/tratamento farmacológico , MicroRNAs/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Anticorpos Bloqueadores/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/metabolismo , Antígeno CTLA-4/metabolismo , Linhagem Celular Tumoral , Cruzamentos Genéticos , Vigilância Imunológica/efeitos dos fármacos , Interferon gama/antagonistas & inibidores , Interferon gama/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Melanoma/imunologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , MicroRNAs/genética , Transplante de Neoplasias , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacosRESUMO
Requirements for CD4+ T cell memory differentiation were analyzed with adoptively transferred SMARTA T cell receptor (TCR) transgenic cells specific for alymphocytic choriomeningitis virus (LCMV) epitope. LCMV-induced effector and memory differentiation of SMARTA cells mimicked the endogenous CD4+ T cell response. In contrast, infection with a recombinant Listeria expressing the LCMV epitope, although resulting initially in massive SMARTA expansion, led to loss of effector function and rapid cell death characterized by high expression of the apoptosis regulator Bim. Defective memory differentiation was seen after stimulation of naive but not memory SMARTA cells, was independent of precursor frequency, and correlated with a lower TCR avidity compared to endogenous responders. In addition, long-lived endogenous CD4+ memory T cells skewed to a higher functional avidity over time. These results support a model in which CD4+ T cell memory differentiation and longevity depend on the strength of the TCR signal during the primary response.
Assuntos
Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Memória Imunológica , Sequência de Aminoácidos , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/transplante , Adesão Celular/genética , Adesão Celular/imunologia , Diferenciação Celular/genética , Linhagem Celular , Proliferação de Células , Chlorocebus aethiops , Cricetinae , Memória Imunológica/genética , Interferon gama/biossíntese , Interleucina-2/biossíntese , Listeria monocytogenes/imunologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dados de Sequência Molecular , Fator de Necrose Tumoral alfa/biossíntese , Células VeroRESUMO
The parameters that modulate the functional capacity of secondary Th1 effector cells are poorly understood. In this study, we employ a serial adoptive transfer model system to show that the functional differentiation and secondary memory potential of secondary CD4+ effector T cells are dependent on the inflammatory environment of the secondary challenge. Adoptive transfer of TCR transgenic lymphocytic choriomeningitis virus (LCMV) Glycoprotein-specific SMARTA memory cells into LCMV-immune hosts, followed by secondary challenge with Listeria monocytogenes recombinantly expressing a portion of the LCMV Glycoprotein (Lm-gp61), resulted in the rapid emergence of SMARTA secondary effector cells with heightened functional avidity (as measured by their ability to make IFNγ in response to ex vivo restimulation with decreasing concentrations of peptide), limited contraction after pathogen clearance and stable maintenance secondary memory T cell populations. In contrast, transfer of SMARTA memory cells into naïve hosts prior to secondary Lm-gp61 challenge, which resulted in a more extended infectious period, resulted in poor functional avidity, increased death during the contraction phase and poor maintenance of secondary memory T cell populations. The modulation of functional avidity during the secondary Th1 response was independent of differences in antigen load or persistence. Instead, the inflammatory environment strongly influenced the function of the secondary Th1 response, as inhibition of IL-12 or IFN-I activity respectively reduced or increased the functional avidity of secondary SMARTA effector cells following rechallenge in a naïve secondary hosts. Our findings demonstrate that secondary effector T cells exhibit inflammation-dependent differences in functional avidity and memory potential, and have direct bearing on the design of strategies aimed at boosting memory T cell responses.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Microambiente Celular/imunologia , Memória Imunológica , Inflamação/imunologia , Animais , Células Cultivadas , Chlorocebus aethiops , Memória Imunológica/genética , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/genética , Células Th1/imunologia , Células VeroRESUMO
Listeria monocytogenes (Lm) is both a life-threatening pathogen of humans and a model organism that is widely used to dissect the mechanisms of innate and adaptive immune resistance to infection. Specific aspects of the immune response to systemic Lm infection can be protective, neutral, or in some cases deleterious. In this review, we seek to provide an overview of the early events during Lm infection that dictate or regulate host innate and adaptive immune responses. We highlight several recent developments that add to our understanding of the complex interplay between inflammatory responses, host susceptibility to infection, and the development of protective immunity.
Assuntos
Listeria monocytogenes/imunologia , Listeriose/imunologia , Imunidade Adaptativa , Animais , Células Dendríticas/imunologia , Humanos , Imunidade Inata , Células Matadoras Naturais/imunologiaRESUMO
IL-2 signals during the primary response to infection are essential in shaping CD8(+) T cell fate decisions. How CD8(+) T cells integrate IL-2 signals in the development of functional memory is not well understood. Because IL-2 induces potent activation of the STAT5 transcription factor, we tested the role of STAT5 in CD8(+) memory T cell differentiation and function using a model system in which STAT5 activity is inducibly abrogated upon CD8(+) T cell activation. We report that STAT5 activity is broadly important for the expansion and effector function of all effector CTL subsets. After pathogen clearance, STAT5 was required for the survival of effector phenotype memory CTLs during the contraction phase. However, despite its role in supporting full primary CD8(+) T cell expansion, and unlike IL-2, STAT5 activity is not required for the development of memory CD8(+) T cells capable of robust secondary expansion upon rechallenge. Our findings highlight differential requirements for survival signals between primary and secondary effector CTL, and demonstrate that IL-2-dependent programming of memory CD8(+) T cells capable of secondary expansion and secondary effector differentiation is largely STAT5 independent.
Assuntos
Memória Imunológica , Fator de Transcrição STAT5/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Animais , Infecções por Arenaviridae/genética , Infecções por Arenaviridae/imunologia , Infecções por Arenaviridae/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/imunologia , Expressão Gênica , Memória Imunológica/genética , Interleucina-2/imunologia , Interleucina-2/metabolismo , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Knockout , Fator de Transcrição STAT5/deficiência , Fator de Transcrição STAT5/genética , Transdução de Sinais , Linfócitos T Citotóxicos/citologiaRESUMO
Following acute infection in some mouse models, CD4+ memory T cells steadily decline over time. Conversely, in humans, CD4+ memory T cells can be maintained for many years at levels similar to CD8+ T cells. Because we previously observed that the longevity of Th1 memory cell survival corresponded to their functional avidity, we hypothesized that secondary challenge, which enriches for high functional avidity Th1 responders, would result in more stable Th1 memory populations. We found that following a heterologous secondary challenge, Th1 memory cells were maintained at stable levels compared with primary Th1 memory cells, showing little to no decline after day 75 postinfection. The improved stability of secondary Th1 memory T cells corresponded to enhanced homeostatic turnover; enhanced trafficking of effector memory Th1 cells to tissue sites of infection, such as the liver; and acquisition or maintenance of high functional avidity following secondary challenge. Conversely, a weaker homologous rechallenge failed to induce a stable secondary Th1 memory population. Additionally, homologous secondary challenge resulted in a transient loss of functional avidity by Th1 memory cells recruited into the secondary response. Our findings suggest that the longevity of Th1 memory T cells is dependent, at least in part, on the combined effects of primary and secondary Ag-driven differentiation. Furthermore, they demonstrate that the quality of the secondary challenge can have profound effects on the longevity and function of the ensuing secondary Th1 memory population.
Assuntos
Imunização Secundária/métodos , Memória Imunológica , Ativação Linfocitária/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Sequência de Aminoácidos , Animais , Sobrevivência Celular/imunologia , Chlorocebus aethiops , Cricetinae , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dados de Sequência Molecular , Células VeroRESUMO
Tumour-host immune interactions lead to complex changes in the tumour microenvironment (TME), impacting progression, metastasis and response to therapy. While it is clear that cancer cells can have the capacity to alter immune landscapes, our understanding of this process is incomplete. Herein we show that endocytic trafficking at the plasma membrane, mediated by the small GTPase ARF6, enables melanoma cells to impose an immunosuppressive TME that accelerates tumour development. This ARF6-dependent TME is vulnerable to immune checkpoint blockade therapy (ICB) but in murine melanoma, loss of Arf6 causes resistance to ICB. Likewise, downregulation of ARF6 in patient tumours correlates with inferior overall survival after ICB. Mechanistically, these phenotypes are at least partially explained by ARF6-dependent recycling, which controls plasma membrane density of the interferon-gamma receptor. Collectively, our findings reveal the importance of endomembrane trafficking in outfitting tumour cells with the ability to shape their immune microenvironment and respond to immunotherapy.
Assuntos
Fator 6 de Ribosilação do ADP , Fatores de Ribosilação do ADP , Membrana Celular , Inibidores de Checkpoint Imunológico , Melanoma , Microambiente Tumoral , Microambiente Tumoral/imunologia , Animais , Humanos , Camundongos , Fatores de Ribosilação do ADP/metabolismo , Fatores de Ribosilação do ADP/genética , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/genética , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma/patologia , Melanoma/imunologia , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Receptor de Interferon gama , Receptores de Interferon/metabolismo , Receptores de Interferon/genética , Transporte Proteico , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Melanoma Experimental/genética , Camundongos Endogâmicos C57BL , FemininoRESUMO
Current influenza vaccine strategies have yet to overcome significant obstacles, including rapid antigenic drift of seasonal influenza viruses, in generating efficacious long-term humoral immunity. Due to the necessity of germinal center formation in generating long-lived high affinity antibodies, the germinal center has increasingly become a target for the development of novel or improvement of less-efficacious vaccines. However, there remains a major gap in current influenza research to effectively target T follicular helper cells during vaccination to alter the germinal center reaction. In this study, we used a heterologous infection or immunization priming strategy to seed an antigen-specific memory CD4+ T cell pool prior to influenza infection in mice to evaluate the effect of recalled memory T follicular helper cells in increased help to influenza-specific primary B cells and enhanced generation of neutralizing antibodies. We found that heterologous priming with intranasal infection with acute lymphocytic choriomeningitis virus (LCMV) or intramuscular immunization with adjuvanted recombinant LCMV glycoprotein induced increased antigen-specific effector CD4+ T and B cellular responses following infection with a recombinant influenza strain that expresses LCMV glycoprotein. Heterologously primed mice had increased expansion of secondary Th1 and Tfh cell subsets, including increased CD4+ TRM cells in the lung. However, the early enhancement of the germinal center cellular response following influenza infection did not impact influenza-specific antibody generation or B cell repertoires compared to primary influenza infection. Overall, our study suggests that while heterologous infection/immunization priming of CD4+ T cells is able to enhance the early germinal center reaction, further studies to understand how to target the germinal center and CD4+ T cells specifically to increase long-lived antiviral humoral immunity are needed.
RESUMO
Adaptive immune resistance (AIR) is a protective process used by cancer to escape elimination by CD8+ T cells. Inhibition of immune checkpoints PD-1 and CTLA-4 specifically target Interferon-gamma (IFNγ)-driven AIR. AIR begins at the plasma membrane where tumor cell-intrinsic cytokine signaling is initiated. Thus, plasma membrane remodeling by endomembrane trafficking could regulate AIR. Herein we report that the trafficking protein ADP-Ribosylation Factor 6 (ARF6) is critical for IFNγ-driven AIR. ARF6 prevents transport of the receptor to the lysosome, augmenting IFNγR expression, tumor intrinsic IFNγ signaling and downstream expression of immunosuppressive genes. In murine melanoma, loss of ARF6 causes resistance to immune checkpoint blockade (ICB). Likewise, low expression of ARF6 in patient tumors correlates with inferior outcomes with ICB. Our data provide new mechanistic insights into tumor immune escape, defined by ARF6-dependent AIR, and support that ARF6-dependent endomembrane trafficking of the IFNγ receptor influences outcomes of ICB.
RESUMO
Little is known regarding how the Oct1 transcription factor regulates target gene expression. Using murine fibroblasts and two target genes, Polr2a and Ahcy, we show that Oct1 recruits the Jmjd1a/KDM3A lysine demethylase to catalyze the removal of the inhibitory histone H3K9 dimethyl mark and block repression. Using purified murine T cells and the Il2 target locus, and a colon cancer cell line and the Cdx2 target locus, we show that Oct1 recruits the NuRD chromatin-remodeling complex to promote a repressed state, but in a regulated manner can switch to a different capacity and mediate Jmjd1a recruitment to block repression. These findings indicate that Oct1 maintains repression through a mechanism involving NuRD and maintains poised gene expression states through an antirepression mechanism involving Jmjd1a. We propose that, rather than acting as a primary trigger of gene activation or repression, Oct1 is a switchable stabilizer of repressed and inducible states.