RESUMO
Idiopathic pulmonary fibrosis (IPF) is a fibrotic age-related chronic lung disease characterized by the accumulation of senescent cells. Whether impaired immune response is responsible for the accumulation of senescent cells in the IPF lung remains unknown. In this study, we characterized the NK phenotype in IPF lungs via flow cytometry using 5-dodecanoylaminofluorescein di-ß-d-galactopyranoside, markers of tissue residence, and chemokine receptors. The effect of the lung microenvironment was evaluated using lung fibroblast (LF) conditioned media (CM), and the bleomycin-induced pulmonary fibrosis mouse model was used to assess the in vivo relationship between NK cells and the accumulation of senescent cells. We found that NK cells from the lower lobe of IPF patients exhibited immune-senescent and impaired CD57-NKG2A+ phenotype. We also observed that culture of NK cells from healthy donors in CM from IPF lower lobe lung fibroblasts induced a senescent-like phenotype and impaired cytotoxic capacity. There is an impaired NK recruitment by LF, and NKs presented decreased migration toward their CM. In addition, NK cell-depleted mice treated with bleomycin showed increased collagen deposition and accumulation of different populations of senescent cells compared with controls. The IPF lung microenvironment induces a dysfunctional NK phenotype limiting the clearance of lung senescent cells and the resolution of lung fibrosis. We propose that impaired NK activity could be one of the mechanisms responsible for perpetuating the accumulation of senescent cells in IPF lungs.
Assuntos
Antineoplásicos , Fibrose Pulmonar Idiopática , Camundongos , Animais , Pulmão/patologia , Fibrose Pulmonar Idiopática/induzido quimicamente , Bleomicina/efeitos adversos , Fibrose , Antineoplásicos/farmacologia , FibroblastosRESUMO
Clonal anergy and depletion of antigen-specific CD8+ T cells are characteristics of immunosuppressed patients such as cancer and post-transplant patients. This has promoted translational research on the adoptive transfer of T cells to restore the antigen-specific cellular immunity in these patients. In the present work, we compared the capability of PBMCs and two types of mature monocyte-derived DCs (moDCs) to prime and to expand ex-vivo antigen-specific CD8+ T cells using culture conditioned media supplemented with IL-7, IL-15, and IL-21. The data obtained suggest that protocols involving moDCs are as efficient as PBMCs-based cultures in expanding antigen-specific CD8+ T cell to ELA and CMV model epitopes. These three gamma common chain cytokines promote the expansion of naïve-like and central memory CD8+ T cells in PBMCs-based cultures and the expansion of effector memory T cells when moDCs were used. Our results provide new insights into the use of media supplemented with IL-7, IL-15, and IL-21 for the in-vitro expansion of early-differentiated antigen-specific CD8+ T cells for immunotherapy purposes.
Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Técnicas de Cultura de Células/métodos , Meios de Cultivo Condicionados/farmacologia , Interleucinas/farmacologia , Adulto , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/química , Citotoxicidade Imunológica , Epitopos de Linfócito T/imunologia , Feminino , Humanos , Memória Imunológica/efeitos dos fármacos , Imunoterapia Adotiva/métodos , Interleucinas/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Transdução de Sinais , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologiaRESUMO
Monitoring literature on the broad spectrum of the human immune response to SARS-CoV-2 is important to understand the mechanisms and progression of COVID-19. The present study undertakes a scoping review of the literature on human immune response to SARS-CoV-2 to determine the characteristics of innate and adaptive responses, as well as biomarkers and cells that play a role in the development of the infection. We searched papers in MEDLINE/PUBMED and EMBASE databases published since December 1st 2019 to to April 9th 2020 from which we selected 56 for this study. We found that the immune response is characterized by high levels of acute phase reactants, neutrophilia, low levels of NKs and eosinophils, lymphopenia, cytokine storm syndrome, exhausted T cells, impaired cytotoxic response, inadequate helper response and production of specific antibodies; concluding that immune dysregulation correlates with disease severity and high mortality.
El seguimiento de la literatura sobre la respuesta inmune humana al SARS-CoV-2 es importante para comprender los mecanismos y la progresión de COVID-19. En el presente estudio se realizó un Scoping Review de la literatura sobre la respuesta inmune humana al SARS-CoV-2 para determinar las características de la respuesta inmune innata y adaptativa, así como biomarcadores y células que juegan un papel en el desarrollo de la infección. Buscamos artículos en las bases de datos MEDLINE / PUBMED y EMBASE publicados desde el 1 de diciembre de 2019 hasta el 9 de abril de 2020, de los cuales seleccionamos 56 publicaciones para este estudio. Encontramos que la respuesta inmune se caracteriza por altos niveles de reactantes de fase aguda, neutrofilia, bajos niveles de NKs y eosinófilos, linfopenia, síndrome de tormenta de citoquinas, linfocitos T agotados, respuesta citotóxica alterada, respuesta T helper inadecuada y producción de anticuerpos específicos. En conclusión, el desequilibrio inmune se correlaciona con la severidad y la mortalidad de la enfermedad.
