RESUMO
The cytokine interleukin (IL)-1ß is a key mediator of antimicrobial immunity as well as autoimmune inflammation. Production of IL-1ß requires transcription by innate immune receptor signaling and maturational cleavage by inflammasomes. Whether this mechanism applies to IL-1ß production seen in T cell-driven autoimmune diseases remains unclear. Here, we describe an inflammasome-independent pathway of IL-1ß production that was triggered upon cognate interactions between effector CD4+ T cells and mononuclear phagocytes (MPs). The cytokine TNF produced by activated CD4+ T cells engaged its receptor TNFR on MPs, leading to pro-IL-1ß synthesis. Membrane-bound FasL, expressed by CD4+ T cells, activated death receptor Fas signaling in MPs, resulting in caspase-8-dependent pro-IL-1ß cleavage. The T cell-instructed IL-1ß resulted in systemic inflammation, whereas absence of TNFR or Fas signaling protected mice from CD4+ T cell-driven autoimmunity. The TNFR-Fas-caspase-8-dependent pathway provides a mechanistic explanation for IL-1ß production and its consequences in CD4+ T cell-driven autoimmune pathology.
Assuntos
Autoimunidade/imunologia , Linfócitos T CD4-Positivos/imunologia , Inflamação/patologia , Interleucina-1beta/metabolismo , Células Mieloides/metabolismo , Animais , Caspase 1/genética , Caspase 8/metabolismo , Células Cultivadas , Células Dendríticas/imunologia , Proteína Ligante Fas/metabolismo , Imunidade Inata/imunologia , Inflamassomos/imunologia , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/imunologia , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Alloreactive memory T cells have been implicated as central drivers of transplant rejection. Perplexingly, innate cytokines, such as IL-6, IL-1ß, and IL-12, are also associated with rejection of organ transplants. However, the pathways of innate immune activation in allogeneic transplantation are unclear. While the role of microbial and cell death products has been previously described, we identified alloreactive memory CD4 T cells as the primary triggers of innate inflammation. Memory CD4 T cells engaged MHC II-mismatched dendritic cells (DCs), leading to the production of innate inflammatory cytokines. This innate inflammation was independent of several pattern recognition receptors and was primarily driven by TNF superfamily ligands expressed by alloreactive memory CD4 T cells. Blocking of CD40L and TNFα resulted in dampened inflammation, and mice genetically deficient in these molecules exhibited prolonged survival of cardiac allografts. Furthermore, myeloid cell and CD8 T cell infiltration into cardiac transplants was compromised in both CD40L- and TNFα-deficient recipients. Strikingly, we found that priming of naive alloreactive CD8 T cells was dependent on licensing of DCs by memory CD4 T cells. This study unravels the key mechanisms by which alloreactive memory CD4 T cells contribute to destructive pathology and transplant rejection.
Assuntos
Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Células Dendríticas , Rejeição de Enxerto , Transplante de Coração , Imunidade Inata , Inflamação , Animais , Rejeição de Enxerto/imunologia , Camundongos , Células Dendríticas/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD4-Positivos/imunologia , Inflamação/imunologia , Imunidade Inata/imunologia , Camundongos Endogâmicos C57BL , Ligante de CD40/imunologia , Ligante de CD40/metabolismo , Células T de Memória/imunologia , Camundongos Knockout , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Citocinas/metabolismo , Citocinas/imunologiaRESUMO
Type 1 diabetes (T1D) results from insulin insufficiency due to islet death and dysfunction following T cell-mediated autoimmune attack. The technical feasibility of durable, functional autologous islet restoration is progressing such that it presents the most likely long-term cure for T1D but cannot succeed without the necessary counterpart of clinically effective therapeutic strategies that prevent grafted islets' destruction by pre-existing anti-islet T cells. While advances have been made in broad immunosuppression to lower off-target effects, the risk of opportunistic infections and cancers remains a concern, especially for well-managed T1D patients. Current immunomodulatory strategies in development focus on autologous Treg expansion, treatments to decrease antigen presentation and T effector (Teff) activation, and broad depletion of T cells with or without hematopoietic stem cell transplants. Emerging strategies harnessing the intensified DNA damage response present in expanding T cells, exacerbating their already high sensitivity to apoptosis to abate autoreactive Teff cells.
Assuntos
Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Ilhotas Pancreáticas , Diabetes Mellitus Tipo 1/tratamento farmacológico , Humanos , Tolerância Imunológica , Linfócitos T ReguladoresRESUMO
T cells play a critical role in immune responses as they specifically recognize peptide/MHC complexes with their T-cell receptors and initiate adaptive immune responses. While T cells are critical for performing appropriate effector functions and maintaining immune memory, they also can cause autoimmunity or neoplasia if misdirected or dysregulated. Thus, T cells must be tightly regulated from their development onward. Maintenance of appropriate T-cell homeostasis is essential to promote protective immunity and limit autoimmunity and neoplasia. This review will focus on the role of cell death in maintenance of T-cell homeostasis and outline novel therapeutic strategies tailored to manipulate cell death to limit T-cell survival (eg, autoimmunity and transplantation) or enhance T-cell survival (eg, vaccination and immune deficiency).
Assuntos
Doenças Autoimunes/imunologia , Rejeição de Enxerto/imunologia , Síndromes de Imunodeficiência/imunologia , Imunoterapia/métodos , Linfócitos T/fisiologia , Animais , Doenças Autoimunes/terapia , Morte Celular , Sobrevivência Celular , Rejeição de Enxerto/prevenção & controle , Homeostase , Humanos , Síndromes de Imunodeficiência/terapia , Transplante , VacinaçãoRESUMO
Antigen-activated lymphocytes undergo extraordinarily rapid cell division in the course of immune responses. We hypothesized that this unique aspect of lymphocyte biology leads to unusual genomic stress in recently antigen-activated lymphocytes and that targeted manipulation of DNA damage-response (DDR) signaling pathways would allow for selective therapeutic targeting of pathological T cells in disease contexts. Consistent with these hypotheses, we found that activated mouse and human T cells display a pronounced DDR in vitro and in vivo. Upon screening a variety of small-molecule compounds, we found that potentiation of p53 (via inhibition of MDM2) or impairment of cell cycle checkpoints (via inhibition of CHK1/2 or WEE1) led to the selective elimination of activated, pathological T cells in vivo. The combination of these strategies [which we termed "p53 potentiation with checkpoint abrogation" (PPCA)] displayed therapeutic benefits in preclinical disease models of hemophagocytic lymphohistiocytosis and multiple sclerosis, which are driven by foreign antigens or self-antigens, respectively. PPCA therapy targeted pathological T cells but did not compromise naive, regulatory, or quiescent memory T-cell pools, and had a modest nonimmune toxicity profile. Thus, PPCA is a therapeutic modality for selective, antigen-specific immune modulation with significant translational potential for diverse immune-mediated diseases.
Assuntos
Dano ao DNA/imunologia , Doenças do Sistema Imunitário/terapia , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/terapia , Etoposídeo/administração & dosagem , Humanos , Doenças do Sistema Imunitário/imunologia , Ativação Linfocitária , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/terapia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Esclerose Múltipla/imunologia , Esclerose Múltipla/terapia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/imunologia , Transdução de Sinais/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologia , Proteína Supressora de Tumor p53/imunologiaRESUMO
There is a direct relationship between the quality of the environment of a workplace and the productivity and efficiency of the work accomplished. Components such as temperature, humidity, ventilation, drafts, lighting, and noise each contribute to the quality of the overall environment and the sense of well-being of those who work there.The modern operating room is a unique workplace with specific, and frequently conflicting, environmental requirements for each of the inhabitants. Even minor disturbances in the internal environment of the operating room can have serious ramifications on the comfort, effectiveness, and safety of each of the inhabitants. A cool, well-ventilated, and dry climate is optimal for many members of the surgical team. Any significant deviation from these objectives raises the risk of decreased efficiency and productivity and adverse surgical outcomes. A warmer, more humid, and quieter environment is necessary for the patient. If these requirements are not met, the risk of surgical morbidity and mortality is increased. An important task for the surgical team is to find the correct balance between these 2 opposed requirements. Several of the components of the operating room environment, especially room temperature and airflow patterns, are easily manipulated by the members of the surgical team. In the following discussion, we will examine these elements to better understand the clinical ramifications of adjustments and accommodations that are frequently made to meet the requirements of both the surgical staff and the patient.
Assuntos
Meio Ambiente , Salas Cirúrgicas/normas , Local de Trabalho/normas , Humanos , Umidade/normas , Iluminação/normas , Saúde Ocupacional/normas , Temperatura , Ventilação/métodos , Ventilação/normasRESUMO
PURPOSE OF REVIEW: Impairment and/or disability resulting from any of a number of etiologies will afflict a significant number of anesthesiologists at some point during their career. The impaired anesthesiologist can be difficult to identify and challenging to manage. Questions will arise as to if, how, and when colleagues, family members, or friends should intercede if significant impairment is suspected.This review will examine the common sources of impairment among anesthesiologists and the professional implications of these conditions. We will discuss the obligations of an anesthesiologist and his/her colleagues when there is sufficient suspicion that he/she might be impaired. RECENT FINDINGS: Substance use disorder remains one of the commonest sources of impairment among both resident and attending anesthesiologists. Other common etiologies of impairment include various physical ailments, major psychiatric disorders, especially depression and burnout, and age related dementia. Many regulatory organizations, healthcare systems, and state licensing agencies have developed programmes and protocols with which to identify and direct into treatment those suspected of significant impairment. SUMMARY: Some degree of impairment will occur to one-third of anesthesiologists during the course of their career. It is important to understand how such impairments might impact the safe practice of anesthesiology.
Assuntos
Anestesiologistas/ética , Esgotamento Profissional/complicações , Transtornos Mentais/complicações , Segurança do Paciente/legislação & jurisprudência , Inabilitação do Médico/legislação & jurisprudência , Transtornos Relacionados ao Uso de Substâncias/complicações , Fatores Etários , Anestesiologistas/legislação & jurisprudência , Esgotamento Profissional/reabilitação , Competência Clínica/legislação & jurisprudência , Atenção à Saúde/legislação & jurisprudência , Pessoas com Deficiência , Humanos , Transtornos Mentais/reabilitação , Transtornos Relacionados ao Uso de Substâncias/reabilitaçãoRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is an inborn disorder of immune regulation caused by mutations affecting perforin-dependent cytotoxicity. Defects in this pathway impair negative feedback between cytotoxic lymphocytes and APCs, leading to prolonged and pathologic activation of T cells. Etoposide, a widely used chemotherapeutic drug that inhibits topoisomerase II, is the mainstay of treatment for HLH, although its therapeutic mechanism remains unknown. We used a murine model of HLH, involving lymphocytic choriomeningitis virus infection of perforin-deficient mice, to study the activity and mechanism of etoposide for treating HLH and found that it substantially alleviated all symptoms of murine HLH and allowed prolonged survival. This therapeutic effect was relatively unique among chemotherapeutic agents tested, suggesting distinctive effects on the immune response. We found that the therapeutic mechanism of etoposide in this model system involved potent deletion of activated T cells and efficient suppression of inflammatory cytokine production. This effect was remarkably selective; etoposide did not exert a direct anti-inflammatory effect on macrophages or dendritic cells, and it did not cause deletion of quiescent naive or memory T cells. Finally, etoposide's immunomodulatory effects were similar in wild-type and perforin-deficient animals. Thus, etoposide treats HLH by selectively eliminating pathologic, activated T cells and may have usefulness as a novel immune modulator in a broad array of immunopathologic disorders.
Assuntos
Etoposídeo/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Animais , Apresentação de Antígeno/efeitos dos fármacos , Apresentação de Antígeno/imunologia , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Proteínas de Ligação a DNA/genética , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Modelos Animais de Doenças , Etoposídeo/administração & dosagem , Interferon gama/biossíntese , Vírus da Coriomeningite Linfocítica , Linfo-Histiocitose Hemofagocítica/genética , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Inibidores da Topoisomerase II/administração & dosagem , Inibidores da Topoisomerase II/farmacologiaRESUMO
The current clinical approach for treating autoimmune diseases is to broadly blunt immune responses as a means of preventing autoimmune pathology. Among the major side effects of this strategy are depressed beneficial immunity and increased rates of infections and tumors. Using the experimental autoimmune encephalomyelitis model for human multiple sclerosis, we report a novel alternative approach for purging autoreactive T cells that spares beneficial immunity. The moderate and temporally limited use of etoposide, a topoisomerase inhibitor, to eliminate encephalitogenic T cells significantly reduces the onset and severity of experimental autoimmune encephalomyelitis, dampens cytokine production and overall pathology, while dramatically limiting the off-target effects on naive and memory adaptive immunity. Etoposide-treated mice show no or significantly ameliorated pathology with reduced antigenic spread, yet have normal T cell and T-dependent B cell responses to de novo antigenic challenges as well as unimpaired memory T cell responses to viral rechallenge. Thus, etoposide therapy can selectively ablate effector T cells and limit pathology in an animal model of autoimmunity while sparing protective immune responses. This strategy could lead to novel approaches for the treatment of autoimmune diseases with both enhanced efficacy and decreased treatment-associated morbidities.
Assuntos
Encefalomielite Autoimune Experimental/imunologia , Depleção Linfocítica , Linfócitos T/imunologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Progressão da Doença , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Etoposídeo/administração & dosagem , Etoposídeo/farmacologia , Feminino , Memória Imunológica , Ativação Linfocitária/efeitos dos fármacos , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Recidiva , Linfócitos T/efeitos dos fármacosRESUMO
PURPOSE OF REVIEW: The average age of anesthesiologists in the USA is increasing. Advancing age is accompanied by challenges and opportunities to the individual anesthesiologist and his/her colleagues. This article will discuss the science behind policies to assure continued competence among these aging physicians and safety for their patients. RECENT FINDINGS: There is growing evidence that aging anesthesiologists may be advantaged by a lifetime of experience but possibly disadvantaged under certain circumstances by lapses in current medical knowledge contributing to medical errors. Policies and procedures are emerging to assist in evaluating the continued competence of aging physicians. SUMMARY: The average age of practicing anesthesiologists in the USA is increasing. As physicians continue to practice into later years, it is critical that innovative continuing medical education programs and objective evaluations of clinical skills and competence focused upon this group continue to be developed to assure public safety.
Assuntos
Envelhecimento/fisiologia , Anestesiologistas , Anestesiologia , Competência Clínica , Fatores Etários , Anestesiologia/legislação & jurisprudência , Humanos , Expectativa de Vida , Erros Médicos , Segurança do Paciente , Aptidão Física , Aposentadoria , Estados Unidos , Recursos HumanosRESUMO
We examined the role of the antiapoptotic molecule Bcl-2 in combating the proapoptotic molecule Bim in control of naive and memory T cell homeostasis using Bcl-2(-/-) mice that were additionally deficient in one or both alleles of Bim. Naive T cells were significantly decreased in Bim(+/-)Bcl-2(-/-) mice, but were largely restored in Bim(-/-)Bcl-2(-/-) mice. Similarly, a synthetic Bcl-2 inhibitor killed wild-type, but not Bim(-/-), T cells. Further, T cells from Bim(+/-)Bcl-2(-/-) mice died rapidly ex vivo and were refractory to cytokine-driven survival in vitro. In vivo, naive CD8(+) T cells required Bcl-2 to combat Bim to maintain peripheral survival, whereas naive CD4(+) T cells did not. In contrast, Bim(+/-)Bcl-2(-/-) mice generated relatively normal numbers of memory T cells after lymphocytic choriomeningitis virus infection. Accumulation of memory T cells in Bim(+/-)Bcl-2(-/-) mice was likely caused by their increased proliferative renewal because of the lymphopenic environment of the mice. Collectively, these data demonstrate a critical role for a balance between Bim and Bcl-2 in controlling homeostasis of naive and memory T cells.
Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Memória Imunológica/fisiologia , Proteínas de Membrana/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Linfócitos T/imunologia , Animais , Proteínas Reguladoras de Apoptose/deficiência , Proteínas Reguladoras de Apoptose/genética , Proteína 11 Semelhante a Bcl-2 , Medula Óssea/imunologia , Medula Óssea/fisiologia , Homeostase , Interleucina-7/deficiência , Ativação Linfocitária , Coriomeningite Linfocítica/imunologia , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcl-2/deficiência , Proteínas Proto-Oncogênicas c-bcl-2/genética , Linfócitos T/fisiologia , TimectomiaRESUMO
IFN-γ is generally believed to be important in the autoimmune pathogenesis of type 1 diabetes (T1D). However, the development of spontaneous ß-cell autoimmunity is unaffected in NOD mice lacking expression of IFN-γ or the IFN-γ receptor (IFNγR), bringing into question the role IFN-γ has in T1D. In the current study, an adoptive transfer model was employed to define the contribution of IFN-γ in CD4(+) versus CD8(+) T cell-mediated ß-cell autoimmunity. NOD.scid mice lacking expression of the IFNγR ß chain (NOD.scid.IFNγRB(null)) developed diabetes following transfer of ß cell-specific CD8(+) T cells alone. In contrast, ß cell-specific CD4(+) T cells alone failed to induce diabetes despite significant infiltration of the islets in NOD.scid.IFNγRB(null) recipients. The lack of pathogenicity of CD4(+) T-cell effectors was due to the resistance of IFNγR-deficient ß cells to inflammatory cytokine-induced cell death. On the other hand, CD4(+) T cells indirectly promoted ß-cell destruction by providing help to CD8(+) T cells in NOD.scid.IFNγRB(null) recipients. These results demonstrate that IFN-γR may play a key role in CD4(+) T cell-mediated ß-cell destruction.
Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Receptores de Interferon/imunologia , Transferência Adotiva , Animais , Autoimunidade , Proliferação de Células , Células Cultivadas , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores de Interferon/deficiência , Receptor de Interferon gamaRESUMO
As acute infections resolve, most effector CD8(+) T cells die, whereas some persist and become memory T cells. Recent work showed that subsets of effector CD8(+) T cells, identified by reciprocal expression of killer cell lectin-like receptor G1 (KLRG1) and CD127, have different lifespans. Similar to previous reports, we found that effector CD8(+) T cells reported to have a longer lifespan (i.e., KLRG1(low)CD127(high)) have increased levels of Bcl-2 compared with their shorter-lived KLRG1(high)CD127(low) counterparts. Surprisingly, we found that these effector KLRG1(low)CD127(high) CD8(+) T cells also had increased levels of Bim compared with KLRG1(high)CD127(low) cells. Similar effects were observed in memory cells, in which CD8(+) central memory T cells expressed higher levels of Bim and Bcl-2 than did CD8(+) effector memory T cells. Using both pharmacologic and genetic approaches, we found that survival of both subsets of effector and memory CD8(+) T cells required Bcl-2 to combat the proapoptotic activity of Bim. Interestingly, inhibition or absence of Bcl-2 led to significantly decreased expression of Bim in surviving effector and memory T cells. In addition, manipulation of Bcl-2 levels by IL-7 or IL-15 also affected expression of Bim in effector CD8(+) T cells. Finally, we found that Bim levels were significantly increased in effector CD8(+) T cells lacking Bax and Bak. Together, these data indicate that cells having the highest levels of Bim are selected against during contraction of the response and that Bcl-2 determines the level of Bim that effector and memory T cells can tolerate.
Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Subpopulações de Linfócitos T/imunologia , Animais , Apoptose , Proteínas Reguladoras de Apoptose/genética , Proteína 11 Semelhante a Bcl-2 , Linfócitos T CD8-Positivos/citologia , Sobrevivência Celular , Genes bcl-2 , Interleucina-15/imunologia , Interleucina-15/metabolismo , Interleucina-7/imunologia , Interleucina-7/metabolismo , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/imunologia , Lectinas Tipo C , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas/genética , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Proteína Killer-Antagonista Homóloga a bcl-2/deficiência , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína X Associada a bcl-2/deficiência , Proteína X Associada a bcl-2/genéticaRESUMO
Following their proliferative expansion and differentiation into effector cells like Th1, Tfh, and T central memory precursors (Tcmp), most effector CD4+ T cells die, while some survive and become memory cells. Here, we explored how Bcl-2 family members controlled the survival of CD4+ T cells during distinct phases of mouse acute LCMV infection. During expansion, we found that Th1 cells dominated the response, downregulated expression of Bcl-2, and did not require Bcl-2 for survival. Instead, they relied on the anti-apoptotic protein, A1 for survival. Similarly, Th17 cells in an EAE model also depended on A1 for survival. However, after the peak of the response, CD4+ effector T cells required Bcl-2 to counteract Bim to aid their transition into memory. This Bcl-2 dependence persisted in established memory CD4+ T cells. Combined, these data show a temporal switch in Bcl-2 family-mediated survival of CD4+ T cells over the course of an immune response. This knowledge can help improve T cell survival to boost immunity and conversely, target pathogenic T cells.
RESUMO
Introduction: Significant evidence suggests a connection between transplant rejection and the presence of high levels of pre-existing memory T cells. Viral infection can elicit viral-specific memory T cells that cross-react with allo-MHC capable of driving allograft rejection in mice. Despite these advances, and despite their critical role in transplant rejection, a systematic study of allo-reactive memory T cells, their specificities, and the role of cross-reactivity with viral antigens has not been performed. Methods: Here, we established a model to identify, isolate, and characterize cross-reactive T cells using Nur77 reporter mice (C57BL/6 background), which transiently express GFP exclusively upon TCR engagement. We infected Nur77 mice with lymphocytic choriomeningitis virus (LCMV-Armstrong) to generate a robust memory compartment, where quiescent LCMV-specific memory CD8+ T cells could be readily tracked with MHC tetramer staining. Then, we transplanted LCMV immune mice with allogeneic hearts and monitored expression of GFP within MHC-tetramer defined viral-specific T cells as an indicator of their ability to cross-react with alloantigens. Results: Strikingly, prior LCMV infection significantly increased the kinetics and magnitude of rejection as well as CD8+ T cell recruitment into allogeneic, but not syngeneic, transplanted hearts, relative to non-infected controls. Interestingly, as early as day 1 after allogeneic heart transplant an average of ~8% of MHC-tetramer+ CD8+ T cells expressed GFP, in contrast to syngeneic heart transplants, where the frequency of viral-specific CD8+ T cells that were GFP+ was <1%. These data show that a significant percentage of viral-specific memory CD8+ T cells expressed T cell receptors that also recognized alloantigens in vivo. Notably, the frequency of cross-reactive CD8+ T cells differed depending upon the viral epitope. Further, TCR sequences derived from cross-reactive T cells harbored distinctive motifs that may provide insight into cross-reactivity and allo-specificity. Discussion: In sum, we have established a mouse model to track viral-specific, allo-specific, and cross-reactive T cells; revealing that prior infection elicits substantial numbers of viral-specific T cells that cross-react to alloantigen, respond very early after transplant, and may promote rapid rejection.
Assuntos
Linfócitos T CD8-Positivos , Viroses , Camundongos , Animais , Camundongos Endogâmicos C57BL , Vírus da Coriomeningite Linfocítica , Receptores de Antígenos de Linfócitos T/genética , Isoantígenos , AloenxertosRESUMO
BACKGROUND: Anesthesiology is among the medical specialties expected to have physician shortage. With little known about older anesthesiologists' work effort and retirement decision making, the American Society of Anesthesiologists participated in a 2006 national survey of physicians aged 50-79 yr. METHODS: Samples of anesthesiologists and other specialists completed a survey of work activities, professional satisfaction, self-defined health and financial status, retirement plans and perspectives, and demographics. A complex survey design enabled adjustments for sampling and response-rate biases so that respondents' characteristics resembled those in the American Medical Association Physician Masterfile. Retirement decision making was modeled with multivariable ordinal logistic regression. Life-table analysis provided a forecast of likely clinical workforce trends over an ensuing 30 yr. RESULTS: Anesthesiologists (N = 3,222; response rate = 37%) reported a mean work week of 49.4 h and a mean retirement age of 62.7 yr, both values similar to those of other older physicians. Work week decreased with age, and part-time work increased. Women worked a shorter work week (mean, 47.9 vs. 49.7 h, P = 0.024), partly due to greater part-time work (20.2 vs. 13.1%, P value less than 0.001). Relative importance of factors reported among those leaving patient care differed by age cohort, subspecialty, and work status. Poor health was cited by 64% of anesthesiologists retiring in their 50s as compared with 43% of those retiring later (P = 0.039). CONCLUSIONS: This survey lends support for greater attention to potentially modifiable factors, such as workplace wellness and professional satisfaction, to prevent premature retirement. The growing trend in part-time work deserves further study.
Assuntos
Anestesiologia/tendências , Tomada de Decisões , Mão de Obra em Saúde/tendências , Médicos/tendências , Aposentadoria/tendências , Fatores Etários , Idoso , Estudos de Coortes , Estudos Transversais , Coleta de Dados/métodos , Feminino , Humanos , Satisfação no Emprego , Masculino , Pessoa de Meia-Idade , Estados UnidosRESUMO
In type 1 diabetes, the breach of central and peripheral tolerance results in autoreactive T cells that destroy insulin-producing, pancreatic beta cells. In this study, we identify a critical subpopulation of dendritic cells responsible for mediating both the cross-presentation of islet Ags to CD8(+) T cells and the direct presentation of beta cell Ags to CD4(+) T cells. These cells, termed merocytic dendritic cells (mcDCs), are more numerous in the NOD mouse and, when Ag-loaded, rescue CD8(+) T cells from peripheral anergy and deletion while stimulating islet-reactive CD4(+) T cells. When purified from the pancreatic lymph nodes of overtly diabetic NOD mice, mcDCs break peripheral T cell tolerance to beta cells in vivo and induce rapid onset type 1 diabetes in the young NOD mouse. Thus, the mcDC subset appears to represent the long-sought APC responsible for breaking peripheral tolerance to beta cell Ags in vivo.
Assuntos
Antígenos/imunologia , Células Dendríticas/imunologia , Diabetes Mellitus Tipo 1/imunologia , Células Secretoras de Insulina/imunologia , Linfócitos T/imunologia , Animais , Antígeno CD11b/imunologia , Antígeno CD11b/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Antígenos CD8/imunologia , Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Apresentação Cruzada/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/transplante , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Citometria de Fluxo , Tolerância Imunológica/imunologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Interferon Tipo I/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Endogâmicos , Camundongos Transgênicos , Linfócitos T/metabolismoRESUMO
In type 1 diabetes (T1D), a break in central and peripheral tolerance results in antigen-specific T cells destroying insulin-producing, pancreatic beta cells. Herein, we discuss the critical sub-population of dendritic cells responsible for mediating both the cross-presentation of islet antigen to CD8(+) T cells and the direct presentation of beta cell antigen to CD4(+) T cells. These cells, termed merocytic dendritic cells (mcDC), are more numerous in non-obese diabetic (NOD), and antigen-loaded mcDC rescue CD8(+) T cells from peripheral anergy and deletion, and stimulate islet-reactive CD4(+) T cells. When purified from the pancreatic lymph nodes of overtly diabetic NOD mice, mcDC can break peripheral T cell tolerance to beta cell antigens in vivo and induce rapid onset T cell-mediated T1D in young NOD mouse. Thus, the mcDC subset appears to represent the long-sought critical antigen-presenting cell responsible for breaking peripheral tolerance to beta cell antigen in vivo.