RESUMO
Whereas pathogen-specific T and B cells are a primary focus of interest during infectious disease, we have used COVID-19 to ask whether their emergence comes at a cost of broader B cell and T cell repertoire disruption. We applied a genomic DNA-based approach to concurrently study the immunoglobulin-heavy (IGH) and T cell receptor (TCR) ß and δ chain loci of 95 individuals. Our approach detected anticipated repertoire focusing for the IGH repertoire, including expansions of clusters of related sequences temporally aligned with SARS-CoV-2-specific seroconversion, and enrichment of some shared SARS-CoV-2-associated sequences. No significant age-related or disease severity-related deficiencies were noted for the IGH repertoire. By contrast, whereas focusing occurred at the TCRß and TCRδ loci, including some TCRß sequence-sharing, disruptive repertoire narrowing was almost entirely limited to many patients aged older than 50 y. By temporarily reducing T cell diversity and by risking expansions of nonbeneficial T cells, these traits may constitute an age-related risk factor for COVID-19, including a vulnerability to new variants for which T cells may provide key protection.
Assuntos
Imunidade Adaptativa , COVID-19 , Cadeias Pesadas de Imunoglobulinas , Receptores de Antígenos de Linfócitos T alfa-beta , Receptores de Antígenos de Linfócitos T , SARS-CoV-2 , Imunidade Adaptativa/genética , Idoso , Linfócitos B/imunologia , COVID-19/genética , COVID-19/imunologia , Loci Gênicos , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , SARS-CoV-2/imunologia , Soroconversão , Linfócitos T/imunologiaRESUMO
Murine intraepithelial γδ T cells include distinct tissue-protective cells selected by epithelial butyrophilin-like (BTNL) heteromers. To determine whether this biology is conserved in humans, we characterized the colonic γδ T cell compartment, identifying a diverse repertoire that includes a phenotypically distinct subset coexpressing T cell receptor Vγ4 and the epithelium-binding integrin CD103. This subset was disproportionately diminished and dysregulated in inflammatory bowel disease, whereas on-treatment CD103+γδ T cell restoration was associated with sustained inflammatory bowel disease remission. Moreover, CD103+Vγ4+cell dysregulation and loss were also displayed by humans with germline BTNL3/BTNL8 hypomorphism, which we identified as a risk factor for penetrating Crohn's disease (CD). Thus, BTNL-dependent selection and/or maintenance of distinct tissue-intrinsic γδ T cells appears to be an evolutionarily conserved axis limiting the progression of a complex, multifactorial, tissue-damaging disease of increasing global incidence.
Assuntos
Butirofilinas , Doenças Inflamatórias Intestinais , Receptores de Antígenos de Linfócitos T gama-delta , Subpopulações de Linfócitos T , Animais , Humanos , Camundongos , Butirofilinas/genética , Colo/imunologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Subpopulações de Linfócitos T/imunologia , Mucosa Intestinal/imunologiaRESUMO
A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-01186-5.
RESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. Some signature traits identify links with other settings of immunoprotection and immunopathology; others, including basophil and plasmacytoid dendritic cell depletion, correlate strongly with disease severity; while a third set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. Hence, contingent upon independent validation in other COVID-19 cohorts, individual traits within this signature may collectively and individually guide treatment options; offer insights into COVID-19 pathogenesis; and aid early, risk-based patient stratification that is particularly beneficial in phasic diseases such as COVID-19.
Assuntos
Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Células Dendríticas/imunologia , Pneumonia Viral/imunologia , Linfócitos T/imunologia , Idoso , Subpopulações de Linfócitos B/imunologia , Basófilos/imunologia , Betacoronavirus , COVID-19 , Estudos de Casos e Controles , Ciclo Celular , Quimiocina CXCL10/imunologia , Quimiocinas/imunologia , Estudos de Coortes , Infecções por Coronavirus/sangue , Progressão da Doença , Feminino , Citometria de Fluxo , Hospitalização , Humanos , Memória Imunológica , Imunofenotipagem , Interleucina-10/imunologia , Interleucina-6/imunologia , Contagem de Leucócitos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Prognóstico , SARS-CoV-2 , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia , Regulação para CimaRESUMO
The intraepithelial lymphocyte (IEL) network of T-cell receptor gammadelta+ (Vgamma5+) dendritic epidermal T cells (DETC) in murine skin down-regulates cutaneous inflammation, although the mechanism is unknown. Thymosin-beta4 (Tbeta4), identified by serial analysis of gene expression as a predominant transcript in gut IEL, encodes both a ubiquitous actin-binding protein (UTbeta4) with demonstrated capacity to inhibit neutrophilic infiltration, and a splice-variant limited to lymphoid tissue (LTbeta4) with unknown bioactivity. Freshly isolated Vgamma5+ DETCs expressed both forms, while only LTbeta4 was preferentially up-regulated after cellular activation in vitro. To compare the anti-inflammatory properties of LTbeta4 and UTbeta4 in the skin in vivo, the biological activities of synthesized polypeptides were assessed using three different strategies: neutrophil infiltration by footpad lambda-carrageenan injection; irritant contact dermatitis to 12-O-tetradecanoylphorbol 13-acetate; and allergic contact dermatitis to 2,4-dinitrofluorobenzene. These studies clearly showed that the anti-inflammatory activities of LTbeta4 were broader and most often stronger than those of UTbeta4. Thus, the activation-responsive expression of the lymph-specific form of Tbeta4 may be one mechanism by which DETC, and possibly other IELs, down-regulate local inflammation.
Assuntos
Anti-Inflamatórios/uso terapêutico , Células Dendríticas/metabolismo , Dermatite de Contato/tratamento farmacológico , Proteínas dos Microfilamentos/uso terapêutico , Timosina/genética , Processamento Alternativo , Animais , Bioensaio , Células Cultivadas , Dermatite Alérgica de Contato/tratamento farmacológico , Dermatite Irritante/tratamento farmacológico , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/análise , Pele/metabolismoRESUMO
Although T cell receptor (TCR)gammadelta+ and TCRalphabeta+ cells are commonly viewed as functionally independent, their relatedness and potential interdependence remain enigmatic. Here we have identified a gene profile that distinguishes mouse gammadelta cell populations from conventional alphabeta T cells. However, this profile was also expressed by sets of unconventional alphabeta T cells. Therefore, whereas TCR specificity determines the involvement of a T cell in an immune response, the cell's functional potential, as assessed by gene expression, does not segregate with the TCR. By monitoring the described gene profile, we show that gammadelta T cell development and function in TCRbeta-deficient mice was impaired because of the absence of alphabeta T cell progenitors. Thus, normal gammadelta cell development is dependent on the development of conventional alphabeta T cells.