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1.
Nat Immunol ; 21(10): 1194-1204, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32895539

RESUMO

Early atherosclerosis depends upon responses by immune cells resident in the intimal aortic wall. Specifically, the healthy intima is thought to be populated by vascular dendritic cells (DCs) that, during hypercholesterolemia, initiate atherosclerosis by being the first to accumulate cholesterol. Whether these cells remain key players in later stages of disease is unknown. Using murine lineage-tracing models and gene expression profiling, we reveal that myeloid cells present in the intima of the aortic arch are not DCs but instead specialized aortic intima resident macrophages (MacAIR) that depend upon colony-stimulating factor 1 and are sustained by local proliferation. Although MacAIR comprise the earliest foam cells in plaques, their proliferation during plaque progression is limited. After months of hypercholesterolemia, their presence in plaques is overtaken by recruited monocytes, which induce MacAIR-defining genes. These data redefine the lineage of intimal phagocytes and suggest that proliferation is insufficient to sustain generations of macrophages during plaque progression.


Assuntos
Aorta/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Placa Aterosclerótica/imunologia , Túnica Íntima/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Movimento Celular , Proliferação de Células , Células Cultivadas , Colesterol/metabolismo , Progressão da Doença , Humanos , Fator Estimulador de Colônias de Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Parabiose , Fagocitose
2.
Nat Immunol ; 19(2): 173-182, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29311694

RESUMO

CD8+ T cell immunosurveillance dynamics influence the outcome of intracellular infections and cancer. Here we used two-photon intravital microscopy to visualize the responses of CD8+ resident memory T cells (TRM cells) within the reproductive tracts of live female mice. We found that mucosal TRM cells were highly motile, but paused and underwent in situ division after local antigen challenge. TRM cell reactivation triggered the recruitment of recirculating memory T cells that underwent antigen-independent TRM cell differentiation in situ. However, the proliferation of pre-existing TRM cells dominated the local mucosal recall response and contributed most substantially to the boosted secondary TRM cell population. We observed similar results in skin. Thus, TRM cells can autonomously regulate the expansion of local immunosurveillance independently of central memory or proliferation in lymphoid tissue.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade nas Mucosas/imunologia , Memória Imunológica/imunologia , Vigilância Imunológica/imunologia , Mucosa/imunologia , Animais , Feminino , Microscopia Intravital , Camundongos , Mucosa/citologia , Pele/imunologia
3.
Nat Immunol ; 17(2): 187-95, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26726812

RESUMO

Studies of repertoires of mouse monoclonal CD4(+) T cells have revealed several mechanisms of self-tolerance; however, which mechanisms operate in normal repertoires is unclear. Here we studied polyclonal CD4(+) T cells specific for green fluorescent protein expressed in various organs, which allowed us to determine the effects of specific expression patterns on the same epitope-specific T cells. Peptides presented uniformly by thymic antigen-presenting cells were tolerated by clonal deletion, whereas peptides excluded from the thymus were ignored. Peptides with limited thymic expression induced partial clonal deletion and impaired effector T cell potential but enhanced regulatory T cell potential. These mechanisms were also active for T cell populations specific for endogenously expressed self antigens. Thus, the immunotolerance of polyclonal CD4(+) T cells was maintained by distinct mechanisms, according to self-peptide expression patterns.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Expressão Gênica , Tolerância Imunológica , Peptídeos/genética , Peptídeos/imunologia , Sequência de Aminoácidos , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Autoantígenos/química , Autoantígenos/genética , Autoantígenos/imunologia , Autoimunidade , Deleção Clonal/genética , Deleção Clonal/imunologia , Epitopos de Linfócito T/química , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Feminino , Genes Reporter , Camundongos , Camundongos Transgênicos , Peptídeos/química , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Timo/imunologia , Timo/metabolismo
4.
Nat Immunol ; 17(3): 304-14, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26829766

RESUMO

The role of anergy, an acquired state of T cell functional unresponsiveness, in natural peripheral tolerance remains unclear. In this study, we found that anergy was selectively induced in fetal antigen-specific maternal CD4(+) T cells during pregnancy. A naturally occurring subpopulation of anergic polyclonal CD4(+) T cells, enriched for self antigen-specific T cell antigen receptors, was also present in healthy hosts. Neuropilin-1 expression in anergic conventional CD4(+) T cells was associated with hypomethylation of genes related to thymic regulatory T cells (Treg cells), and this correlated with their ability to differentiate into Foxp3(+) Treg cells that suppressed immunopathology. Thus, our data suggest that not only is anergy induction important in preventing autoimmunity but also it generates the precursors for peripheral Treg cell differentiation.


Assuntos
Autoimunidade/imunologia , Diferenciação Celular/imunologia , Anergia Clonal/imunologia , Histocompatibilidade Materno-Fetal/imunologia , Tolerância Periférica/imunologia , Células Precursoras de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Artrite Experimental/imunologia , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Citocinas/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Genes Codificadores da Cadeia alfa de Receptores de Linfócitos T , Immunoblotting , Masculino , Camundongos , Camundongos Knockout , Neuropilina-1/metabolismo , Gravidez , Receptores de Antígenos de Linfócitos T/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tolerância a Antígenos Próprios , Timócitos/imunologia
5.
Immunity ; 48(2): 327-338.e5, 2018 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-29466758

RESUMO

Immunosurveillance of secondary lymphoid organs (SLO) is performed by central memory T cells that recirculate through blood. Resident memory T (Trm) cells remain parked in nonlymphoid tissues and often stably express CD69. We recently identified Trm cells within SLO, but the origin and phenotype of these cells remains unclear. Using parabiosis of "dirty" mice, we found that CD69 expression is insufficient to infer stable residence of SLO Trm cells. Restimulation of nonlymphoid memory CD8+ T cells within the skin or mucosa resulted in a substantial increase in bona fide Trm cells specifically within draining lymph nodes. SLO Trm cells derived from emigrants from nonlymphoid tissues and shared some transcriptional and phenotypic signatures associated with nonlymphoid Trm cells. These data indicate that nonlymphoid cells can give rise to SLO Trm cells and suggest vaccination strategies by which memory CD8+ T cell immunosurveillance can be regionalized to specific lymph nodes.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Linfonodos/imunologia , Animais , Antígenos CD/análise , Antígenos de Diferenciação de Linfócitos T/análise , Feminino , Lectinas Tipo C/análise , Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL
6.
Proc Natl Acad Sci U S A ; 121(31): e2320303121, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39008691

RESUMO

Influenza viruses pose a significant burden on global human health. Influenza has a broad cellular tropism in the airway, but how infection of different epithelial cell types impacts replication kinetics and burden in the airways is not fully understood. Using primary human airway cultures, which recapitulate the diverse epithelial cell landscape of the human airways, we investigated the impact of cell type composition on virus tropism and replication kinetics. Cultures were highly diverse across multiple donors and 30 independent differentiation conditions and supported a range of influenza replication. Although many cell types were susceptible to influenza, ciliated and secretory cells were predominantly infected. Despite the strong tropism preference for secretory and ciliated cells, which consistently make up 75% or more of infected cells, only ciliated cells were associated with increased virus production. Surprisingly, infected secretory cells were associated with overall reduced virus output. The disparate response and contribution to influenza virus production could be due to different pro- and antiviral interferon-stimulated gene signatures between ciliated and secretory populations, which were interrogated with single-cell RNA sequencing. These data highlight the heterogeneous outcomes of influenza virus infections in the complex cellular environment of the human airway and the disparate impacts of infected cell identity on multiround burst size, even among preferentially infected cell types.


Assuntos
Células Epiteliais , Influenza Humana , Tropismo Viral , Replicação Viral , Humanos , Influenza Humana/virologia , Replicação Viral/fisiologia , Células Epiteliais/virologia , Células Epiteliais/metabolismo , Cílios/virologia , Cílios/metabolismo , Células Cultivadas , Mucosa Respiratória/virologia , Mucosa Respiratória/citologia
7.
Immunity ; 42(1): 95-107, 2015 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-25601203

RESUMO

T cell receptor (TCR) cross-reactivity between major histocompatibility complex II (MHCII)-binding self and foreign peptides could influence the naive CD4(+) T cell repertoire and autoimmunity. We found that nonamer peptides that bind to the same MHCII molecule only need to share five amino acids to cross-react on the same TCR. This property was biologically relevant because systemic expression of a self peptide reduced the size of a naive cell population specific for a related foreign peptide by deletion of cells with cross-reactive TCRs. Reciprocally, an incompletely deleted naive T cell population specific for a tissue-restricted self peptide could be triggered by related microbial peptides to cause autoimmunity. Thus, TCR cross-reactivity between similar self and foreign peptides can reduce the size of certain foreign peptide-specific T cell populations and might allow T cell populations specific for tissue-restricted self peptides to cause autoimmunity after infection.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Esclerose Múltipla/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Fragmentos de Peptídeos/imunologia , Animais , Autoimunidade , Células Cultivadas , Seleção Clonal Mediada por Antígeno , Reações Cruzadas , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mutagênese Sítio-Dirigida , Mutação/genética , Glicoproteína Mielina-Oligodendrócito/genética , Fragmentos de Peptídeos/genética , Proteômica , Receptores de Antígenos de Linfócitos T/metabolismo
8.
J Immunol ; 205(5): 1449-1460, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32737148

RESUMO

Optimal ex vivo expansion protocols of tumor-specific T cells followed by adoptive cell therapy must yield T cells able to home to tumors and effectively kill them. Our previous study demonstrated ex vivo activation in the presence of IL-12-induced optimal CD8+ T cell expansion and melanoma regression; however, adverse side effects, including autoimmunity, can occur. This may be due to transfer of high-avidity self-specific T cells. In this study, we compared mouse low- and high-avidity T cells targeting the tumor Ag tyrosinase-related protein 2 (TRP2). Not surprisingly, high-avidity T cells provide superior tumor control, yet low-avidity T cells can promote tumor regression. The addition of IL-12 during in vitro expansion boosts low-avidity T cell responsiveness, tumor regression, and prevents T cell exhaustion. In this study, we demonstrate that IL-12-primed T cells are resistant to PD-1/PD-L1-mediated suppression and retain effector function. Importantly, IL-12 preconditioning prevented exhaustion as LAG-3, PD-1, and TOX were decreased while simultaneously increasing KLRG1. Using intravital imaging, we also determined that high-avidity T cells have sustained contacts with intratumoral dendritic cells and tumor targets compared with low-avidity T cells. However, with Ag overexpression, this defect is overcome, and low-avidity T cells control tumor growth. Taken together, these data illustrate that low-avidity T cells can be therapeutically beneficial if cocultured with IL-12 cytokine during in vitro expansion and highly effective in vivo if Ag is not limiting. Clinically, low-avidity T cells provide a safer alternative to high-avidity, TCR-engineered T cells, as IL-12-primed, low-avidity T cells cause less autoimmune vitiligo.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Interleucina-12/imunologia , Ativação Linfocitária/imunologia , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Animais , Antígenos de Neoplasias/imunologia , Autoimunidade/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Imunoterapia Adotiva/métodos , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia
9.
Proc Natl Acad Sci U S A ; 116(7): 2640-2645, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30679280

RESUMO

Established T cell dysfunction is a barrier to antitumor responses, and checkpoint blockade presumably reverses this. Many patients fail to respond to treatment and/or develop autoimmune adverse events. The underlying reason for T cell responsiveness remains elusive. Here, we show that susceptibility to checkpoint blockade is dependent on the activation status of T cells. Newly activated self-specific CD8 T cells respond to checkpoint blockade and cause autoimmunity, which is mitigated by inhibiting the mechanistic target of rapamycin. However, once tolerance is established, self-specific CD8 T cells display a gene signature comparable to tumor-specific CD8 T cells in a fixed state of dysfunction. Tolerant self-specific CD8 T cells do not respond to single or combinatorial dosing of anti-CTLA4, anti-PD-L1, anti-PD-1, anti-LAG-3, and/or anti-TIM-3. Despite this, T cell responsiveness can be induced by vaccination with cognate antigen, which alters the previously fixed transcriptional signature and increases antigen-sensing machinery. Antigenic reeducation of tolerant T cells synergizes with checkpoint blockade to generate functional CD8 T cells, which eliminate tumors without concomitant autoimmunity and are transcriptionally distinct from classic effector T cells. These data demonstrate that responses to checkpoint blockade are dependent on the activation state of a T cell and show that checkpoint blockade-insensitive CD8 T cells can be induced to respond to checkpoint blockade with robust antigenic stimulation to participate in tumor control.


Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Reprogramação Celular , Animais , Antígenos/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Proliferação de Células , Tolerância Imunológica , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL
10.
PLoS Pathog ; 15(9): e1008077, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31557273

RESUMO

Influenza A virus (IAV) is a seasonal pathogen with the potential to cause devastating pandemics. IAV infects multiple epithelial cell subsets in the respiratory tract, eliciting damage to the lungs. Clearance of IAV is primarily dependent on CD8+ T cells, which must balance control of the infection with immunopathology. Using a virus expressing Cre recombinase to permanently label infected cells in a Cre-inducible reporter mouse, we previously discovered infected club cells that survive both lytic virus replication and CD8+ T cell-mediated clearance. In this study, we demonstrate that ciliated epithelial cells, type I and type II alveolar cells can also become survivor cells. Survivor cells are stable in the lung long-term and demonstrate enhanced proliferation compared to uninfected cells. When we investigated how survivor cells evade CD8+ T cell killing we observed that survivor cells upregulated the inhibitory ligand PD-L1, but survivor cells did not use PD-L1 to evade CD8+ T cell killing. Instead our data suggest that survivor cells are not inherently resistant to CD8+ T cell killing, but instead no longer present IAV antigen and cannot be detected by CD8+ T cells. Finally, we evaluate the failure of CD8+ T cells to kill these previously infected cells. This work demonstrates that additional cell types can survive IAV infection and that these cells robustly proliferate and are stable long term. By sparing previously infected cells, the adaptive immune system may be minimizing pathology associated with IAV infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Evasão da Resposta Imune , Influenza Humana/imunologia , Influenza Humana/virologia , Imunidade Adaptativa , Animais , Antígeno B7-H1/imunologia , Proliferação de Células , Sobrevivência Celular/imunologia , Citotoxicidade Imunológica , Humanos , Imunidade Celular , Vírus da Influenza A/imunologia , Vírus da Influenza A/patogenicidade , Influenza Humana/patologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/imunologia
11.
Nat Immunol ; 10(11): 1185-92, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19783989

RESUMO

Programmed death 1 (PD-1) is an inhibitory molecule expressed on activated T cells; however, the biological context in which PD-1 controls T cell tolerance remains unclear. Using two-photon laser-scanning microscopy, we show here that unlike naive or activated islet antigen-specific T cells, tolerized islet antigen-specific T cells moved freely and did not swarm around antigen-bearing dendritic cells (DCs) in pancreatic lymph nodes. Inhibition of T cell antigen receptor (TCR)-driven stop signals depended on continued interactions between PD-1 and its ligand, PD-L1, as antibody blockade of PD-1 or PD-L1 resulted in lower T cell motility, enhanced T cell-DC contacts and caused autoimmune diabetes. Blockade of the immunomodulatory receptor CTLA-4 did not alter T cell motility or abrogate tolerance. Thus, PD-1-PD-L1 interactions maintain peripheral tolerance by mechanisms fundamentally distinct from those of CTLA-4.


Assuntos
Antígenos de Superfície/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Antígeno B7-1/imunologia , Tolerância Imunológica , Glicoproteínas de Membrana/imunologia , Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Animais , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígenos de Superfície/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Antígeno B7-1/metabolismo , Antígeno B7-H1 , Antígeno CTLA-4 , Movimento Celular , Células Dendríticas/imunologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Transplante das Ilhotas Pancreáticas , Ativação Linfocitária , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Peptídeos/metabolismo , Receptor de Morte Celular Programada 1
12.
Curr Diab Rep ; 21(6): 20, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33956235

RESUMO

PURPOSE OF REVIEW: Programmed death-1 (PD-1) is an inhibitory receptor that controls T and B cell proliferation and function through interacting with its ligand PD-L1 or PD-L2. PD-1/PD-L1 blockade reboots anti-tumor immunity and is currently used to treat > 15 different types of cancer. However, the response rate is not at 100% and some patients relapse. Importantly, up to 37% of patients treated with PD-1/PD-L1 blocking antibodies develop immune-related adverse events, including overt autoimmunity, such as type 1 diabetes (T1D). Herein, we discuss the role of PD-1, PD-L1, and PD-L2 signaling in pre-clinical models of T1D, including recent work from our laboratory. RECENT FINDINGS: We highlight ongoing efforts to harness PD-1/PD-L1 signaling and treat autoimmunity. We also evaluate studies aimed at defining biomarkers that could reliably predict the development of immune-related adverse events after clinical PD-1/PD-L1 blockade. With increasing use of PD-1 blockade in the clinic, onset of autoimmunity is a growing health concern. In this review, we discuss what is known about the role of PD-1 pathway signaling in T1D and comment on ongoing efforts to identify patients at risk of T1D development after PD-1 pathway blockade.


Assuntos
Diabetes Mellitus Tipo 1 , Neoplasias , Autoimunidade , Humanos , Ativação Linfocitária , Transdução de Sinais
13.
J Immunol ; 202(9): 2535-2545, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30858199

RESUMO

Naive CD4+ T lymphocytes differentiate into various Th cell subsets following TCR binding to microbial peptide:MHC class II (p:MHCII) complexes on dendritic cells (DCs). The affinity of the TCR interaction with p:MHCII plays a role in Th differentiation by mechanisms that are not completely understood. We found that low-affinity TCRs biased mouse naive T cells to become T follicular helper (Tfh) cells, whereas higher-affinity TCRs promoted the formation of Th1 or Th17 cells. We explored the basis for this phenomenon by focusing on IL-2R signaling, which is known to promote Th1 and suppress Tfh cell differentiation. SIRP⍺+ DCs produce abundant p:MHCII complexes and consume IL-2, whereas XCR1+ DCs weakly produce p:MHCII but do not consume IL-2. We found no evidence, however, of preferential interactions between Th1 cell-prone, high-affinity T cells and XCR1+ DCs or Tfh cell-prone, low-affinity T cells and SIRP⍺+ DCs postinfection with bacteria expressing the peptide of interest. Rather, high-affinity T cells sustained IL-2R expression longer and expressed two novel Th cell differentiation regulators, Eef1e1 and Gbp2, to a higher level than low-affinity T cells. These results suggest that TCR affinity does not influence Th cell differentiation by biasing T cell interactions with IL-2-consuming DCs, but instead, directly regulates genes in naive T cells that control the differentiation process.


Assuntos
Diferenciação Celular/imunologia , Proteínas de Ligação ao GTP/imunologia , Regulação da Expressão Gênica/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Fatores de Alongamento de Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Células Th1/imunologia , Células Th2/imunologia , Animais , Diferenciação Celular/genética , Células Dendríticas/citologia , Células Dendríticas/imunologia , Proteínas de Ligação ao GTP/genética , Regulação da Expressão Gênica/genética , Subunidade alfa de Receptor de Interleucina-2/genética , Camundongos , Camundongos Knockout , Fatores de Alongamento de Peptídeos/genética , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Células Th1/citologia , Células Th2/citologia
14.
J Immunol ; 203(4): 844-852, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31324724

RESUMO

Programmed death-1 (PD-1) inhibits T and B cell function upon ligand binding. PD-1 blockade revolutionized cancer treatment, and although numerous patients respond, some develop autoimmune-like symptoms or overt autoimmunity characterized by autoantibody production. PD-1 inhibition accelerates autoimmunity in mice, but its role in regulating germinal centers (GC) is controversial. To address the role of PD-1 in the GC reaction in type 1 diabetes, we used tetramers to phenotype insulin-specific CD4+ T and B cells in NOD mice. PD-1 or PD-L1 deficiency, and PD-1 but not PD-L2 blockade, unleashed insulin-specific T follicular helper CD4+ T cells and enhanced their survival. This was concomitant with an increase in GC B cells and augmented insulin autoantibody production. The effect of PD-1 blockade on the GC was reduced when mice were treated with a mAb targeting the insulin peptide:MHC class II complex. This work provides an explanation for autoimmune side effects following PD-1 pathway inhibition and suggests that targeting the self-peptide:MHC class II complex might limit autoimmunity arising from checkpoint blockade.


Assuntos
Autoimunidade/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Receptor de Morte Celular Programada 1/imunologia , Animais , Antígeno B7-H1/imunologia , Diabetes Mellitus Experimental/imunologia , Feminino , Centro Germinativo/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos NOD
15.
Blood ; 131(16): 1858-1869, 2018 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-29463561

RESUMO

Conditioning-induced damage of the intestinal tract plays a critical role during the onset of acute graft-versus-host disease (GVHD). Therapeutic interference with these early events of GVHD is difficult, and currently used immunosuppressive drugs mainly target donor T cells. However, not donor T cells but neutrophils reach the sites of tissue injury first, and therefore could be a potential target for GVHD prevention. A detailed analysis of neutrophil fate during acute GVHD and the effect on T cells is difficult because of the short lifespan of this cell type. By using a novel photoconverter reporter system, we show that neutrophils that had been photoconverted in the ileum postconditioning later migrated to mesenteric lymph nodes (mLN). This neutrophil migration was dependent on the intestinal microflora. In the mLN, neutrophils colocalized with T cells and presented antigen on major histocompatibility complex (MHC)-II, thereby affecting T cell expansion. Pharmacological JAK1/JAK2 inhibition reduced neutrophil influx into the mLN and MHC-II expression, thereby interfering with an early event in acute GVHD pathogenesis. In agreement with this finding, neutrophil depletion reduced acute GVHD. We conclude that neutrophils are attracted to the ileum, where the intestinal barrier is disrupted, and then migrate to the mLN, where they participate in alloantigen presentation. JAK1/JAK2-inhibition can interfere with this process, which provides a potential therapeutic strategy to prevent early events of tissue damage-related innate immune cell activation and, ultimately, GVHD.


Assuntos
Comunicação Celular/imunologia , Doença Enxerto-Hospedeiro/imunologia , Íleo/imunologia , Linfonodos/imunologia , Mesentério/imunologia , Neutrófilos/imunologia , Doença Aguda , Animais , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/genética , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/patologia , Íleo/patologia , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/genética , Janus Quinase 1/imunologia , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Janus Quinase 2/imunologia , Linfonodos/patologia , Mesentério/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Infiltração de Neutrófilos/efeitos dos fármacos , Infiltração de Neutrófilos/genética , Infiltração de Neutrófilos/imunologia , Neutrófilos/patologia , Inibidores de Proteínas Quinases/farmacologia
16.
J Immunol ; 200(2): 477-482, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29255075

RESUMO

Organ transplants are rapidly rejected because T cells in the recipient attack the foreign MHC molecules on the graft. The robustness of the T cell response to histoincompatible tissue is not understood. We found that mice have many small T cell populations with Ag receptors specific for a foreign MHC class II molecule type loaded with peptides from leukocytes from the graft. These T cells proliferated modestly after skin transplantation and underwent relatively weak functional differentiation compared with T cells stimulated by a vaccine. Thus, the potency of the T cell response to histoincompatible tissue is likely due to many small T cell populations responding weakly to hundreds of MHC-bound peptides from graft-derived leukocytes.


Assuntos
Aloenxertos/imunologia , Rejeição de Enxerto/imunologia , Antígenos de Histocompatibilidade/imunologia , Leucócitos/imunologia , Peptídeos/imunologia , Linfócitos T/imunologia , Animais , Antígenos de Histocompatibilidade/química , Antígenos de Histocompatibilidade/metabolismo , Imunofenotipagem , Leucócitos/metabolismo , Camundongos , Camundongos Knockout , Peptídeos/química , Peptídeos/metabolismo , Ligação Proteica/imunologia , Multimerização Proteica , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
17.
J Immunol ; 199(1): 33-38, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28539428

RESUMO

Despite accounting for 10-30% of the T cell population in mice and humans, the role of dual TCR-expressing T cells in immunity remains poorly understood. It has been hypothesized that dual TCR T cells pose an autoimmune hazard by allowing self-reactive TCRs to escape thymic selection. We revisited this hypothesis using the NOD murine model of type 1 diabetes. We bred NOD mice hemizygous at both TCRα and ß (TCRα+/- ß+/-) loci, rendering them incapable of producing dual TCR T cells. We found that the lack of dual TCRα expression skewed the insulin-specific thymocyte population toward greater regulatory T (Treg) cell commitment, resulting in a more tolerogenic Treg to conventional T cell ratio and protection from diabetes. These data support a novel hypothesis by which dual TCR expression can promote autoimmunity by limiting agonist selection of self-reactive thymocytes into the Treg cell lineage.


Assuntos
Autoimunidade , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T Reguladores/imunologia , Animais , Diabetes Mellitus Tipo 1/imunologia , Camundongos , Camundongos Endogâmicos NOD , Linfócitos T Reguladores/fisiologia , Timócitos/imunologia
18.
Int J Mol Sci ; 20(9)2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31052404

RESUMO

Vulvodynia is a remarkably prevalent chronic pain condition of unknown etiology. An increase in numbers of vulvar mast cells often accompanies a clinical diagnosis of vulvodynia and a history of allergies amplifies the risk of developing this condition. We previously showed that repeated exposures to oxazolone dissolved in ethanol on the labiar skin of mice led to persistent genital sensitivity to pressure and a sustained increase in labiar mast cells. Here we sensitized female mice to the hapten dinitrofluorobenzene (DNFB) dissolved in saline on their flanks, and subsequently challenged them with the same hapten or saline vehicle alone for ten consecutive days either on labiar skin or in the vaginal canal. We evaluated tactile ano-genital sensitivity, and tissue inflammation at serial timepoints. DNFB-challenged mice developed significant, persistent tactile sensitivity. Allergic sites showed mast cell accumulation, infiltration of resident memory CD8+CD103+ T cells, early, localized increases in eosinophils and neutrophils, and sustained elevation of serum Immunoglobulin E (IgE). Therapeutic intra-vaginal administration of Δ9-tetrahydrocannabinol (THC) reduced mast cell accumulation and tactile sensitivity. Mast cell-targeted therapeutic strategies may therefore provide new ways to manage and treat vulvar pain potentially instigated by repeated allergenic exposures.


Assuntos
Analgésicos não Narcóticos/uso terapêutico , Dronabinol/uso terapêutico , Hipersensibilidade/complicações , Mastócitos/efeitos dos fármacos , Tato , Vulvodinia/tratamento farmacológico , Analgésicos não Narcóticos/farmacologia , Animais , Dinitrofluorbenzeno/toxicidade , Dronabinol/farmacologia , Feminino , Imunoglobulina E/sangue , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Mastócitos/imunologia , Camundongos , Vulvodinia/etiologia , Vulvodinia/fisiopatologia
19.
BMC Infect Dis ; 17(1): 595, 2017 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-28851294

RESUMO

BACKGROUND: Current antiretroviral therapy (ART) used to treat human immunodeficiency virus (HIV) patients is life-long because it only suppresses de novo infections. Recent efforts to eliminate HIV have tested the ability of a number of agents to reactivate ('Kick') the well-known latent reservoir. This approach is rooted in the assumption that once these cells are reactivated the host's immune system itself will eliminate ('Kill') the virus. While many agents have been shown to reactivate large quantities of the latent reservoir, the impact on the size of the latent reservoir has been negligible. This suggests that the immune system is not sufficient to eliminate reactivated reservoirs. Thus, there is a need for more emphasis on 'kill' strategies in HIV cure research, and how these might work in combination with current or future kick strategies. METHODS: We conducted a landscape review of HIV 'cure' clinical trials using 'kick and kill' approaches. We identified and reviewed current available clinical trial results in human participants as well as ongoing and planned clinical trials. We dichotomized trials by whether they did not include or include a 'kill' agent. We extracted potential reasons why the 'kill' is missing from current 'kick and kill' strategies. We subsequently summarized and reviewed current 'kill' strategies have entered the phase of clinical trial testing in human participants and highlighted those with the greatest promise. RESULTS: The identified 'kick' trials only showed promise on surrogate measures activating latent T-cells, but did not show any positive effects on clinical 'cure' measures. Of the 'kill' agents currently being tested in clinical trials, early results have shown small but meaningful proportions of participants remaining off ART for several months with broadly neutralizing antibodies, as well as agents for regulating immune cell responses. A similar result was also recently observed in a trial combining a conventional 'kick' with a vaccine immune booster ('kill'). CONCLUSION: While an understanding of the efficacy of each individual component is crucial, no single 'kick' or 'kill' agent is likely to be a fully effective cure. Rather, the solution is likely found in a combination of multiple 'kick and kill' interventions.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Anticorpos Neutralizantes/farmacologia , Ensaios Clínicos como Assunto , Epigênese Genética , Infecções por HIV/fisiopatologia , Infecções por HIV/transmissão , HIV-1/patogenicidade , HIV-1/fisiologia , Humanos , Terapia de Alvo Molecular , Latência Viral/efeitos dos fármacos , Latência Viral/imunologia
20.
J Immunol ; 194(8): 3551-3555, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25769925

RESUMO

Programmed death-1 (PD-1) promotes T cell tolerance. Despite therapeutically targeting this pathway for chronic infections and tumors, little is known about how different T cell subsets are affected during blockade. We examined PD-1/PD ligand 1 (PD-L1) regulation of self-antigen-specific CD4 and CD8 T cells in autoimmune-susceptible models. PD-L1 blockade increased insulin-specific effector CD4 T cells in type 1 diabetes. However, anergic islet-specific CD4 T cells were resistant to PD-L1 blockade. Additionally, PD-L1 was critical for induction, but not maintenance, of CD8 T cell intestinal tolerance. PD-L1 blockade enhanced functionality of effector T cells, whereas established tolerant or anergic T cells were not dependent on PD-1/PD-L1 signaling to remain unresponsive. This highlights the existence of Ag-experienced T cell subsets that do not rely on PD-1/PD-L1 regulation. These findings illustrate how positive treatment outcomes and autoimmunity development during PD-1/PD-L1 inhibition are linked to the differentiation state of a T cell.


Assuntos
Doenças Autoimunes/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Anergia Clonal , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Suscetibilidade a Doenças/imunologia , Suscetibilidade a Doenças/patologia , Feminino , Tolerância Imunológica/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Receptor de Morte Celular Programada 1/genética , Transdução de Sinais/genética
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