CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-γ

Publication date: Available online 5 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Otavio Cabral-Marques, Tabata Takahashi França, Ashraf Al-Sbiei, Lena Friederike Schimke, Taj Ali Khan, Claudia Feriotti, Tania Alves da Costa, Osvaldo Reis Junior, Cristina Worm Weber, Janaíra Fernandes Ferreira, Fabiola Scancetti Tavares, Claudia Valente, Regina Sumiko Watanabe Di Gesu, Asif Iqbal, Gabriela Riemekasten, Gustavo Pessini Amarante-Mendes, José Alexandre Marzagão Barbuto, Beatriz Tavares Costa-Carvalho, Paulo Vitor Soeiro Pereira, Maria J. Fernandez-Cabezudo, Vera Lucia Garcia Calich, Luigi D. Notarangelo, Troy R. Torgerson, Basel K. al-Ramadi, Hans D. Ochs, Antonio Condino-Neto
BackgroundPatients with X-linked Hyper-IgM syndrome (X-HIGM) due to CD40 ligand (CD40L) deficiency often present episodic, cyclic or chronic neutropenia, suggesting abnormal neutrophil development in the absence of CD40L-CD40 interaction. However, even when not neutropenic and despite immunoglobulin (Ig) replacement therapy, CD40L-deficient patients are susceptible to life-threatening infections caused by opportunistic pathogens, suggesting impaired function of phagocytes and the need of novel therapeutic approaches.ObjectivesTo analyze whether peripheral neutrophils from CD40L-deficient patients display functional defects and to explore the in vitro effects of recombinant human interferon (rhIFN)-γ on neutrophil function.MethodsWe investigated the microbicidal activity, respiratory burst and transcriptome profile of neutrophils from CD40L-deficient patients. In addition, we evaluated whether the lack of CD40L in mice also affects neutrophil function.ResultsNeutrophils from CD40L-deficient patients exhibited defective respiratory burst and microbicidal activity which were improved in vitro by rhIFN-γ, but not soluble CD40L (sCD40L). Moreover, neutrophils from patients showed reduced CD16 protein expression and a dysregulated transcriptome suggestive of impaired differentiation. Similar to CD40L-deficient patients, CD40L-knockout mice were found to have impaired neutrophil responses. In parallel, we demonstrated that sCD40L induces the promyelocytic cell line HL-60 to proliferate and mature by regulating the expression of genes of the same gene ontology categories (e.g. cell differentiation) when compared to those dysregulated in peripheral blood neutrophils from CD40L-deficient patients.ConclusionOur data suggest a non-redundant role of CD40L-CD40 interaction in neutrophil development and function that could be improved in vitro by rhIFN-γ, indicating a potential novel therapeutic application for this cytokine.

Teaser

Neutrophils from CD40L-deficient patients exhibit defective development and function that suggest an important role of CD40L-CD40 interaction for neutrophil maturation. These defects improve following in vitro exposure to rhIFN-γ.


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