RESUMO
Upon Ag encounter, T cells can rapidly divide and form an effector population, which plays an important role in fighting acute infections. In humans, little is known about the molecular markers that distinguish such effector cells from other T cell populations. To address this, we investigated the molecular profile of T cells present in individuals with active tuberculosis (ATB), where we expect Ag encounter and expansion of effector cells to occur at higher frequency in contrast to Mycobacterium tuberculosis-sensitized healthy IGRA+ individuals. We found that the frequency of HLA-DR+ cells was increased in circulating CD4 T cells of ATB patients, and was dominantly expressed in M. tuberculosis Ag-specific CD4 T cells. We tested and confirmed that HLA-DR is a marker of recently divided CD4 T cells upon M. tuberculosis Ag exposure using an in vitro model examining the response of resting memory T cells from healthy IGRA+ to Ags. Thus, HLA-DR marks a CD4 T cell population that can be directly detected ex vivo in human peripheral blood, whose frequency is increased during ATB disease and contains recently divided Ag-specific effector T cells. These findings will facilitate the monitoring and study of disease-specific effector T cell responses in the context of ATB and other infections.
Assuntos
Mycobacterium tuberculosis , Tuberculose , Linfócitos T CD4-Positivos/imunologia , Antígenos HLA-DR , HumanosRESUMO
Dengue virus (DENV) can cause diseases ranging from dengue fever (DF) to more severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Whether antiviral T cells contribute to the protection against or pathogenesis of severe disease is not well defined. Here, we identified antigen-specific IL-10+IFN-γ+ double-positive (DP) CD4 T cells during acute DENV infection. While the transcriptomic signatures of DP cells partially overlapped with those of cytotoxic and type 1 regulatory CD4 T cells, the majority of them were non-cytotoxic/Tr1 and included IL21, IL22, CD109, and CCR1. Although we observed a higher frequency of DP cells in DHF, the transcriptomic profile of DP cells was similar in DF and DHF, suggesting that DHF is not associated with the altered phenotypic or functional attributes of DP cells. Overall, this study revealed a DENV-specific DP cell subset in patients with acute dengue disease and argues against altered DP cells as a determinant of DHF.
Assuntos
Vírus da Dengue/imunologia , Regulação da Expressão Gênica/imunologia , Interferon gama/imunologia , Interleucina-10/imunologia , Dengue Grave/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Antígenos CD/genética , Antígenos CD/imunologia , Estudos de Casos e Controles , Vírus da Dengue/patogenicidade , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Humanos , Interferon gama/genética , Interleucina-10/genética , Interleucinas/genética , Interleucinas/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Receptores CCR1/genética , Receptores CCR1/imunologia , Dengue Grave/genética , Dengue Grave/patologia , Dengue Grave/virologia , Índice de Gravidade de Doença , Transdução de Sinais , Linfócitos T Citotóxicos/virologia , Linfócitos T Reguladores/virologia , Transcriptoma/imunologia , Interleucina 22RESUMO
Accumulating evidence demonstrates that CD8+ T cells contribute to protection from severe dengue virus (DENV) disease and vaccine efficacy. Nevertheless, molecular programs associated with DENV-specific CD8+ T cell subsets have not been defined. Here, we studied the transcriptomic profiles of human DENV-specific CD8+ T cells isolated after stimulation with DENV epitopes from donors who had been infected with DENV multiple times and would therefore be expected to have significant levels of adaptive immunity. We found that DENV-specific CD8+ T cells mainly consisted of effector memory subsets, namely CD45RA-CCR7- effector memory (Tem) and CD45RA+CCR7- effector memory re-expressing CD45RA (Temra) cells, which enacted specific gene expression profiles upon stimulation with cognate antigens. DENV-specific CD8+ T cell subsets in general, and Temra cells in particular, were fully activated and polyfunctional, yet associated with relatively narrow transcriptional responses. Furthermore, we found that DENV-specific CD8+ Tem and Temra cells showed some unique T cell receptor features in terms of overlap and variable (V) gene usage. This study provides a transcriptomic definition of DENV-specific activated human CD8+ T cell subsets and defines a benchmark profile that vaccine-specific responses could aim to reproduce.