RESUMO
Calcitriol and 9-cis retinoic acid (9cRA) play a fundamental role in shaping the adaptive immune response by altering the Ig profile and the differentiation of B cells, controlled by their corresponding nuclear receptors, VDR and RAR. Herein, after the establishment of a plasmablast differentiation culture, we investigated how both ligands modulate human naïve B cell differentiation and to which extent VDR/RXR and RAR/RXR signaling interferes. Calcitriol and 9cRA mediated activation of purified naïve B cells resulted in a strong differentiation of CD27+ CD38+ plasmablasts and antibody secretion. The significant IgA response was preceded by a strong induction of α-germline transcription (GLT). Induction of αGLT and consecutively IgA secretion driven by calcitriol is a novel observation and we show by magnetic chromatin IP that this was mediated by recruitment of the VDR to the TGF-ß promoter thus inducing TGF-ß expression. Finally, as revealed by transcriptomic profiling calcitriol and 9cRA modulate several signals required for differentiation and isotype switching in a noncompeting but rather additive manner. Calcitriol and 9cRA participate in the control of the IgA response in human activated naïve B cells. The balance between both ligands may be an important factor in channeling humoral immune responses toward a protective direction.
Assuntos
Alitretinoína/imunologia , Alitretinoína/farmacologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Calcitriol/imunologia , Calcitriol/farmacologia , Imunoglobulina A/biossíntese , Imunidade Adaptativa/efeitos dos fármacos , Linfócitos B/citologia , Sítios de Ligação/genética , Ligante de CD40/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Cultivadas , Proteínas de Ligação ao GTP/genética , Expressão Gênica , Humanos , Switching de Imunoglobulina/efeitos dos fármacos , Switching de Imunoglobulina/imunologia , Interleucina-4/imunologia , Ligantes , Ativação Linfocitária , Plasmócitos/citologia , Plasmócitos/efeitos dos fármacos , Plasmócitos/imunologia , Regiões Promotoras Genéticas , Proteína 2 Glutamina gama-Glutamiltransferase , Receptores de Calcitriol/imunologia , Receptores do Ácido Retinoico/imunologia , Receptores X de Retinoides/imunologia , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta1/biossíntese , Fator de Crescimento Transformador beta1/genética , Transglutaminases/genética , Vitamina D3 24-Hidroxilase/genéticaRESUMO
BACKGROUND: Vitamin A regulates the adaptive immune response and a modulatory impact on type I allergy is discussed. The cellular mechanisms are largely unknown. OBJECTIVE: To determine the vitamin A-responding specific lymphocyte reaction in vivo. METHODS: Antigen-specific B and T lymphocytes were analyzed in an adoptive transfer airway inflammation mouse model in response to 9-cis retinoic acid (9cRA) and after lymphocyte-specific genetic targeting of the receptor RARα. Flow cytometry, quantitative PCR, next-generation sequencing, and specific Ig-ELISA were used to characterize the cells functionally. RESULTS: Systemic 9cRA profoundly enhanced the specific IgA-secreting B-cell frequencies in the lung tissue and serum IgA while reducing serum IgE concentrations. RARα overexpression in antigen-specific B cells promoted differentiation into plasmablasts at the expense of germinal center B cells. In antigen-specific T cells, RARα strongly promoted the differentiation of T follicular helper cells followed by an enhanced germinal center response. CONCLUSIONS: 9cRA signaling via RARα impacts the allergen-specific immunoglobulin response directly by the differentiation of B cells and indirectly by promoting T follicular helper cells.