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1.
J Immunol ; 206(7): 1505-1514, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33658297

RESUMO

IKZF1 (IKAROS) is essential for normal lymphopoiesis in both humans and mice. Previous Ikzf1 mouse models have demonstrated the dual role for IKZF1 in both B and T cell development and have indicated differential requirements of each zinc finger. Furthermore, mutations in IKZF1 are known to cause common variable immunodeficiency in patients characterized by a loss of B cells and reduced Ab production. Through N-ethyl-N-nitrosourea mutagenesis, we have discovered a novel Ikzf1 mutant mouse with a missense mutation (L132P) in zinc finger 1 (ZF1) located in the DNA binding domain. Unlike other previously reported murine Ikzf1 mutations, this L132P point mutation (Ikzf1L132P ) conserves overall protein expression and has a B cell-specific phenotype with no effect on T cell development, indicating that ZF1 is not required for T cells. Mice have reduced Ab responses to immunization and show a progressive loss of serum Igs compared with wild-type littermates. IKZF1L132P overexpressed in NIH3T3 or HEK293T cells failed to localize to pericentromeric heterochromatin and bind target DNA sequences. Coexpression of wild-type and mutant IKZF1, however, allows for localization to pericentromeric heterochromatin and binding to DNA indicating a haploinsufficient mechanism of action for IKZF1L132P Furthermore, Ikzf1+/L132P mice have late onset defective Ig production, similar to what is observed in common variable immunodeficiency patients. RNA sequencing revealed a total loss of Hsf1 expression in follicular B cells, suggesting a possible functional link for the humoral immune response defects observed in Ikzf1L132P/L132P mice.


Assuntos
Linfócitos B/imunologia , Imunodeficiência de Variável Comum/genética , Fator de Transcrição Ikaros/genética , Mutação Puntual/genética , Animais , Formação de Anticorpos , Células HEK293 , Haploinsuficiência , Fatores de Transcrição de Choque Térmico/genética , Fatores de Transcrição de Choque Térmico/metabolismo , Humanos , Fator de Transcrição Ikaros/metabolismo , Imunoglobulinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Células NIH 3T3
2.
Proc Natl Acad Sci U S A ; 114(26): E5216-E5225, 2017 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-28607084

RESUMO

T-cell immunity requires extremely rapid clonal proliferation of rare, antigen-specific T lymphocytes to form effector cells. Here we identify a critical role for ETAA1 in this process by surveying random germ line mutations in mice using exome sequencing and bioinformatic annotation to prioritize mutations in genes of unknown function with potential effects on the immune system, followed by breeding to homozygosity and testing for immune system phenotypes. Effector CD8+ and CD4+ T-cell formation following immunization, lymphocytic choriomeningitis virus (LCMV) infection, or herpes simplex virus 1 (HSV1) infection was profoundly decreased despite normal immune cell development in adult mice homozygous for two different Etaa1 mutations: an exon 2 skipping allele that deletes Gly78-Leu119, and a Cys166Stop truncating allele that eliminates most of the 877-aa protein. ETAA1 deficiency decreased clonal expansion cell autonomously within the responding T cells, causing no decrease in their division rate but increasing TP53-induced mRNAs and phosphorylation of H2AX, a marker of DNA replication stress induced by the ATM and ATR kinases. Homozygous ETAA1-deficient adult mice were otherwise normal, healthy, and fertile, although slightly smaller, and homozygotes were born at lower frequency than expected, consistent with partial lethality after embryonic day 12. Taken together with recently reported evidence in human cancer cell lines that ETAA1 activates ATR kinase through an exon 2-encoded domain, these findings reveal a surprisingly specific requirement for this ATR activator in adult mice restricted to rapidly dividing effector T cells. This specific requirement may provide new ways to suppress pathological T-cell responses in transplantation or autoimmunity.


Assuntos
Antígenos de Superfície/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Divisão Celular/imunologia , Imunidade Celular , Mutação , Animais , Antígenos de Superfície/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Divisão Celular/genética , Herpes Simples/genética , Herpes Simples/imunologia , Herpes Simples/patologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/patologia , Vírus da Coriomeningite Linfocítica/genética , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Mutantes , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologia
3.
Immunology ; 154(3): 522-532, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29411880

RESUMO

Acquisition of T-cell central tolerance involves distinct pathways of self-antigen presentation to thymocytes. One pathway termed indirect presentation requires a self-antigen transfer step from thymic epithelial cells (TECs) to bone marrow-derived cells before the self-antigen is presented to thymocytes. The role of indirect presentation in central tolerance is context-dependent, potentially due to variation in self-antigen expression, processing and presentation in the thymus. Here, we report experiments in mice in which TECs expressed a membrane-bound transgenic self-antigen, hen egg lysozyme (HEL), from either the insulin (insHEL) or thyroglobulin (thyroHEL) promoter. Intrathymic HEL expression was less abundant and more confined to the medulla in insHEL mice compared with thyroHEL mice. When indirect presentation was impaired by generating mice lacking MHC class II expression in bone marrow-derived antigen-presenting cells, insHEL-mediated thymocyte deletion was abolished, whereas thyroHEL-mediated deletion occurred at a later stage of thymocyte development and Foxp3+ regulatory T-cell differentiation increased. Indirect presentation increased the strength of T-cell receptor signalling that both self-antigens induced in thymocytes, as assessed by Helios expression. Hence, indirect presentation limits the differentiation of naive and regulatory T cells by promoting deletion of self-reactive thymocytes.


Assuntos
Apresentação de Antígeno/imunologia , Diferenciação Celular , Seleção Clonal Mediada por Antígeno/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Timócitos/citologia , Timócitos/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Autoantígenos/imunologia , Biomarcadores , Expressão Gênica , Tolerância Imunológica , Imunofenotipagem , Camundongos , Camundongos Knockout , Fenótipo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Timócitos/metabolismo , Timo/citologia , Timo/imunologia
4.
Am J Pathol ; 186(9): 2254-61, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27427419

RESUMO

Chronic intestinal pseudo-obstruction (CIPO) is a rare but life-threatening disease characterized by severe intestinal dysmotility. Histopathologic studies in CIPO patients have identified several different mechanisms that appear to be involved in the dysmotility, including defects in neurons, smooth muscle, or interstitial cells of Cajal. Currently there are few mouse models of the various forms of CIPO. We generated a mouse with a point mutation in the RNA recognition motif of the Nup35 gene, which encodes a component of the nuclear pore complex. Nup35 mutants developed a severe megacolon and exhibited a reduced lifespan. Histopathologic examination revealed a degenerative myopathy that developed after birth and specifically affected smooth muscle in the colon; smooth muscle in the small bowel and the bladder were not affected. Furthermore, no defects were found in enteric neurons or interstitial cells of Cajal. Nup35 mice are likely to be a valuable model for the subtype of CIPO characterized by degenerative myopathy. Our study also raises the possibility that Nup35 polymorphisms could contribute to some cases of CIPO.


Assuntos
Pseudo-Obstrução do Colo/genética , Modelos Animais de Doenças , Doenças Musculares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Mutação Puntual , Animais , Doença Crônica , Pseudo-Obstrução do Colo/patologia , Imuno-Histoquímica , Camundongos , Camundongos Mutantes , Músculo Liso/patologia , Doenças Musculares/patologia
5.
J Immunol ; 195(5): 2263-72, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26195812

RESUMO

CD8(+) T cells that recognize virus-derived peptides presented on MHC class I are vital antiviral effectors. Such peptides presented by any given virus vary greatly in immunogenicity, allowing them to be ranked in an immunodominance hierarchy. However, the full range of parameters that determine immunodominance and the underlying mechanisms remain unknown. In this study, we show across a range of vaccinia virus strains, including the current clonal smallpox vaccine, that the ability of a strain to spread systemically correlated with reduced immunodominance. Reduction in immunodominance was observed both in the lymphoid system and at the primary site of infection. Mechanistically, reduced immunodominance was associated with more robust priming and especially priming in the spleen. Finally, we show this is not just a property of vaccine and laboratory strains of virus, because an association between virulence and immunodominance was also observed in isolates from an outbreak of zoonotic vaccinia virus that occurred in Brazil.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Vacina Antivariólica/imunologia , Vaccinia virus/imunologia , Vacínia/imunologia , Sequência de Aminoácidos , Animais , Antígenos Virais/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Linhagem Celular , Epitopos de Linfócito T/imunologia , Feminino , Interações Hospedeiro-Patógeno/imunologia , Epitopos Imunodominantes/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Camundongos Endogâmicos C57BL , Especificidade da Espécie , Baço/imunologia , Baço/metabolismo , Baço/virologia , Vacínia/virologia , Vaccinia virus/classificação , Vaccinia virus/fisiologia , Zoonoses/virologia
6.
Immunol Cell Biol ; 94(4): 357-66, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26510893

RESUMO

Thymocytes that bind strongly to self-antigens are prevented from becoming naive T cells by several mechanisms. They undergo clonal deletion at two stages of development; wave 1 in immature thymocytes lacking the medulla-homing chemokine receptor, CCR7, or wave 2 in more mature CCR7(+) thymocytes. Alternatively, self-reactive thymocytes upregulate Foxp3 to become T-regulatory cells. Here, we describe the differential timing of the two waves of deletion and Foxp3 upregulation relative to the immature proliferating stage. Proliferating thymocytes were pulse-labeled in normal C57BL/6 mice with 5-ethynyl-2'-deoxyuridine (EdU). Thymocytes progressed into wave 1 (CCR7(-)) and wave 2 (CCR7(+)) of clonal deletion ~2 and 5 days after proliferation, respectively. Foxp3 upregulation occurred between 4 and 8 days after proliferation, predominantly in thymocytes with a Helios(+) CCR7(+) phenotype. These findings establish a timeline that suggests that wave 1 of clonal deletion occurs in the thymic cortex, whereas wave 2 and Foxp3 upregulation both occur in the thymic medulla.


Assuntos
Diferenciação Celular , Seleção Clonal Mediada por Antígeno , Linfócitos T Reguladores/imunologia , Timócitos/imunologia , Timo/imunologia , Animais , Autoantígenos/imunologia , Proliferação de Células , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CCR7/metabolismo , Timo/anatomia & histologia , Fatores de Transcrição/metabolismo , Regulação para Cima
7.
Nat Commun ; 12(1): 2782, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33986293

RESUMO

Chronic stimulation of CD8+ T cells triggers exhaustion, a distinct differentiation state with diminished effector function. Exhausted cells exist in multiple differentiation states, from stem-like progenitors that are the key mediators of the response to checkpoint blockade, through to terminally exhausted cells. Due to its clinical relevance, there is substantial interest in defining the pathways that control differentiation and maintenance of these subsets. Here, we show that chronic antigen induces the anergy-associated transcription factor EGR2 selectively within progenitor exhausted cells in both chronic LCMV and tumours. EGR2 enables terminal exhaustion and stabilizes the exhausted transcriptional state by both direct EGR2-dependent control of key exhaustion-associated genes, and indirect maintenance of the exhausted epigenetic state. We show that EGR2 is a regulator of exhaustion that epigenetically and transcriptionally maintains the differentiation competency of progenitor exhausted cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Anergia Clonal/imunologia , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Linfopoese/fisiologia , Animais , Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Proteína 2 de Resposta de Crescimento Precoce/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
8.
Surg Neurol Int ; 7: 65, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27382522
9.
J Exp Med ; 208(1): 149-65, 2011 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-21220452

RESUMO

Effective vaccine adjuvants must induce expression of major histocompatibility (MHC) class II proteins and the costimulatory molecule CD86 on dendritic cells (DCs). However, some adjuvants elicit production of cytokines resulting in adverse inflammatory consequences. Development of agents that selectively increase MHC class II and CD86 expression without triggering unwanted cytokine production requires a better understanding of the molecular mechanisms influencing the production and degradation of MHC class II and CD86 in DCs. Here, we investigate how CD83, an immunoglobulin protein expressed on the surface of mature DCs, promotes MHC class II and CD86 expression. Using mice with an N-ethyl-N-nitrosourea-induced mutation eliminating the transmembrane (TM) region of CD83, we found that the TM domain of CD83 enhances MHC class II and CD86 expression by blocking MHC class II association with the ubiquitin ligase MARCH1. The TM region of CD83 blocks interleukin 10-driven, MARCH1-dependent ubiquitination and degradation of MHC class II and CD86 in DCs. Exploiting this posttranslational pathway for boosting MHC class II and CD86 expression on DCs may provide an opportunity to enhance the immunogenicity of vaccines.


Assuntos
Antígenos CD/imunologia , Antígeno B7-2/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Imunoglobulinas/imunologia , Interleucina-10/imunologia , Glicoproteínas de Membrana/imunologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Sequência de Aminoácidos , Animais , Antígenos CD/química , Antígenos CD/genética , Sequência de Bases , Membrana Celular/imunologia , Células Dendríticas/imunologia , Células HEK293 , Humanos , Imunoglobulinas/química , Imunoglobulinas/genética , Masculino , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Camundongos , Dados de Sequência Molecular , Alinhamento de Sequência , Ubiquitina-Proteína Ligases/imunologia , Antígeno CD83
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