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CD4⁺ cell-dependent granuloma formation in humanized mice infected with mycobacteria

Author:
Heuts, Frank, Gavier-Widén, Dolores, Carow, Berit, Juarez, Julius, Wigzell, Hans, Rottenberg, Martin E.
Source:
Proceedings of the National Academy of Sciences of the United States of America 2013 v.110 no.16 pp. 6482-6487
ISSN:
0027-8424
Subject:
Mycobacterium bovis, Mycobacterium tuberculosis, T-lymphocytes, encapsulation, giant cells, granuloma, humans, immune response, liver, lungs, macrophages, mice, microbial load, necrosis, noninfectious diseases, stem cells, tuberculosis, tumor necrosis factors
Abstract:
We have used humanized mice, in which human immune cells differentiate de novo from transplanted cord blood progenitor cells, to study the human immune responses to infection with Mycobacterium bovis bacillus Calmette–Guérin and Mycobacterium tuberculosis . Granulomas with a core containing giant cells, human CD68 ⁺ macrophages, and high bacilli numbers surrounded by a layer of CD3 ⁺ T cells and a fibrotic response encapsulating the lesions were observed in livers and lungs from bacillus Calmette–Guérin-infected humanized mice but not in nonhumanized infected controls. Paradoxically, humanized mice contained higher mycobacterial numbers in organs than nonhumanized controls. The enhancement of bacterial load was mediated by human CD4 ⁺ cells and associated to an increased expression of Programmed Death-1 protein and CD57 on T cells, molecules associated with inhibition and senescence. The lesions from mice depleted of CD4 ⁺ cells were scarcer, minimal, and irregular compared with those from mice depleted of CD8 ⁺ cells or nondepleted controls. Granulomas of bacillus Calmette–Guérin-infected humanized mice administered with a TNF-neutralizing TNF receptor fusion molecule preserved their structure, but contained higher levels of intracellular bacilli. Extended necrosis was observed in granulomas from M. tuberculosis - but not bacillus Calmette–Guérin-infected humanized mice. Our data indicate that humanized mice can be used as a model to study the formation and maintenance of human granuloma in tuberculosis and other infectious or noninfectious diseases.
Agid:
1736325