Date Published: January 29, 2008
Publisher: Public Library of Science
Author(s): Martin Rottman, Claire Soudais, Guillaume Vogt, Laurent Renia, Jean-François Emile, Hélène Decaluwe, Jean-Louis Gaillard, Jean-Laurent Casanova, Adrian J Thrasher
Abstract: BackgroundInterferon-γ receptor 1 (IFN-γR1) deficiency is a life-threatening inherited disorder, conferring predisposition to mycobacterial diseases. Haematopoietic stem cell transplantation (HSCT) is the only curative treatment available, but is hampered by a very high rate of graft rejection, even with intra-familial HLA-identical transplants. This high rejection rate is not seen in any other congenital disorders and remains unexplained. We studied the underlying mechanism in a mouse model of HSCT for IFN-γR1 deficiency.Methods and FindingsWe demonstrated that HSCT with cells from a syngenic C57BL/6 Ifngr1+/+ donor engrafted well and restored anti-mycobacterial immunity in naive, non-infected C57BL/6 Ifngr1−/− recipients. However, Ifngr1−/− mice previously infected with Mycobacterium bovis bacillus Calmette-Guérin (BCG) rejected HSCT. Like infected IFN-γR1-deficient humans, infected Ifngr1−/− mice displayed very high serum IFN-γ levels before HSCT. The administration of a recombinant IFN-γ-expressing AAV vector to Ifngr1−/− naive recipients also resulted in HSCT graft rejection. Transplantation was successful in Ifngr1−/− × Ifng−/− double-mutant mice, even after BCG infection. Finally, efficient antibody-mediated IFN-γ depletion in infected Ifngr1−/− mice in vivo allowed subsequent engraftment.ConclusionsHigh serum IFN-γ concentration is both necessary and sufficient for graft rejection in IFN-γR1-deficient mice, inhibiting the development of heterologous, IFN-γR1-expressing, haematopoietic cell lineages. These results confirm that IFN-γ is an anti-haematopoietic cytokine in vivo. They also pave the way for HSCT management in IFN-γR1-deficient patients through IFN-γ depletion from the blood. They further raise the possibility that depleting IFN-γ may improve engraftment in other settings, such as HSCT from a haplo-identical or unrelated donor.
Partial Text: Complete deficiency of the ligand-binding chain of the interferon-γ receptor (IFN-γR1) is an autosomal recessive disorder described in 1996 as the first genetic aetiology of the syndrome of Mendelian Susceptibility to Mycobacterial Diseases (“MSMD”: MIM 209950) [1–3]. Causal mutations either abrogate cell surface IFN-γR1 expression [4,5] or prevent IFN-γ recognition due to the production of surface-expressed, non-functional receptors . Both types of IFN-γR1 deficiency result in a complete loss of cellular responses to IFN-γ. This disorder confers a profound and selective susceptibility to weakly virulent mycobacteria, such as Mycobacterium bovis bacillus Calmette Guérin (BCG) vaccines and environmental mycobacteria , as reviewed in . Humans are also susceptible to the more virulent M. tuberculosis [7,8]. Other infectious diseases are rare, with the exception of salmonellosis, which has been diagnosed in several patients . Listeriosis and a few viral diseases were each diagnosed in single patients [7,10]. Humans do not produce mature granulomas in response to mycobacteria, and instead display poorly delimited, poorly differentiated, multibacillary tissue lesions . They present with early-onset, disseminated, recurrent, and multiple mycobacterial infections. Most patients die in early childhood, with only one-third surviving to the age of 15 years .
We have shown that the surface expression of functional IFN-γR1 in the haematopoietic compartment alone—actually in only about half of that compartment—is sufficient to protect mice against BCG infection. Similarly, Yap and Sher previously showed that IFN-γR1 expression in the haematopoietic compartment was sufficient to restore resistance to the intracellular macrophage-tropic bacterium Listeria monocytogenes in IFN-γR1-deficient mice . However, they also showed that IFN-γR1 expression on both haematopoietic and non-haematopoietic cells was required to confer resistance to the macrophage-tropic intracellular protozoon Toxoplasma gondii . Consistent with these findings, Dal Canto and Virgin showed that IFN-γ acted directly on both haematopoietic and non-haematopoietic cells during infection with the medial smooth muscle murine tropic γ-herpesvirus-68 . Thus, despite the almost ubiquitous expression of IFN-γR1 on both haematopoietic and non-haematopoietic cells [39–41], BCG infection can be controlled—as attested by bacterial killing, granuloma structure, and animal survival—by the restricted action of IFN-γ on the haematopoietic compartment. Results obtained in our murine model are consistent with data from patients with complete IFN-γR1 deficiency undergoing HSCT [12–15] and demonstrate that susceptibility to BCG, and by extension to other mycobacteria, is a haematopoietic disease in persons with IFN-γR1 deficiency. In mice and humans, the extra-haematopoietic expression of IFN-γR1 is redundant for anti-mycobacterial protective immunity.