RESUMEN
The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.
Asunto(s)
Interferón gamma/inmunología , Interleucina-10/inmunología , SARS-CoV-2/inmunología , Células TH1/inmunología , Vitamina D/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Líquido del Lavado Bronquioalveolar/citología , COVID-19/inmunología , COVID-19/patología , Complemento C3a/inmunología , Complemento C3b/inmunología , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Activación de Linfocitos/inmunología , Receptores de Calcitriol/metabolismo , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/patología , Síndrome de Dificultad Respiratoria/virología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/inmunología , Transcripción Genética/genéticaRESUMEN
Vitamin D is a steroid hormone classically involved in the calcium metabolism and bone homeostasis. Recently, new and interesting aspects of vitamin D metabolism has been elucidated, namely the special role of the skin, the metabolic control of liver hydroxylase CYP2R1, the specificity of 1α-hydroxylase in different tissues and cell types and the genomic, non-genomic and epigenomic effects of vitamin D receptor, which will be addressed in the present review. Moreover, in the last decades, several extraskeletal effects which can be attributed to vitamin D have been shown. These beneficial effects will be here summarized, focusing on the immune system and cardiovascular system.