Human CD40L deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ

Publication date: Available online 20 August 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Otavio Cabral-Marques, Rodrigo Nalio Ramos, Lena F. Schimke, Taj Ali Khan, Eduardo Pinheiro Amaral, Caio César Barbosa Bomfim, Osvaldo Reis Junior, Tabata Takahashi França, Christina Arslanian, Joanna Darck Carola Correia Lima, Cristina Worm Weber, Janaíra Fernandes Ferreira, Fabiola Scancetti Tavares, Jing Sun, Maria Regina D´Imperio Lima, Marília Seelaender, Vera Lucia Garcia Calich, José Alexandre Marzagão Barbuto, Beatriz Tavares Costa-Carvalho, Gabriela Riemekasten, Gisela Seminario, Liliana Bezrodnik, Luigi Notarangelo, Troy R. Torgerson, Hans D. Ochs, Antonio Condino-Neto
BackgroundCD40 ligand (CD40L) deficiency predisposes to opportunistic infections, including those caused by fungi and intracellular bacteria. Studies of CD40L-deficient patients reveal the critical role of CD40L-CD40 interaction for the function of T-, B-, and dendritic cells. However, the consequences of CD40L deficiency on macrophage function remain to be investigated.ObjectivesTo determine the impact of CD40L absence on monocytes-derived macrophage (MDMs) responses.MethodsAfter observing the improvement of refractory disseminated mycobacterial infection in a CD40L-deficient patient by recombinant human IFN-γ (rhIFN-γ) adjuvant therapy, we investigated macrophage functions from CD40L-deficient patients. We analyzed killing activity, oxidative burst, cytokine production, and in vitro effects that rhIFN-γ and soluble CD40L (sCD40L) treatment had on macrophages. In addition, the impact of CD40L absence on the macrophage transcriptome before and after rhIFN-γ treatment was studied.ResultsMacrophages from CD40L-deficient patient exhibited defective fungicidal activity and reduced oxidative burst, both of which improved in the presence of rhIFN-γ but not sCD40L. In contrast, rhIFN-γ and sCD40L ameliorate impaired production of inflammatory cytokines. Furthermore, rhIFN-γ reversed defective control of M. tuberculosis proliferation by patient macrophages. The absence of CD40L dysregulated the macrophage transcriptome, which was improved by rhIFN-γ. Additionally, rhIFN-γ increased expression levels of pattern recognition receptors such as TLR1 and TLR2, dectin 1 and DC-SIGN in both controls' and patients' macrophages.ConclusionAbsence of CD40L impairs macrophage development and function. In addition, the improvement of macrophage immune responses by IFN-γ suggests this cytokine as a potential therapeutic option for patients with CD40L deficiency.Clinical ImplicationsThe absence of CD40L impairs macrophage differentiation and function, and its lack contributes to increased susceptibility of CD40L-deficient patients to life threatening infections. Furthermore, rhIFN-γ improves the function of macrophages from CD40L-deficient patients, indicating this cytokine as a potential new adjuvant therapy.

Teaser

Human CD40L deficiency dysregulates the macrophage transcriptome causing functional defects, including defective microbicidal activity, reduced oxidative burst, and impaired production of inflammatory cytokines that are improved by exogenous IFN-γ.


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