CD44 is a macrophage binding site for Mycobacterium tuberculosis that mediates macrophage recruitment and protective immunity against tuberculosis
Jaklien C. Leemans, … , Ronald van der Neut, Tom van der Poll
Jaklien C. Leemans, … , Ronald van der Neut, Tom van der Poll
Published March 1, 2003
Citation Information: J Clin Invest. 2003;111(5):681-689. https://doi.org/10.1172/JCI16936.
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Article Cell biology

CD44 is a macrophage binding site for Mycobacterium tuberculosis that mediates macrophage recruitment and protective immunity against tuberculosis

Abstract

Cell migration and phagocytosis are both important for controlling Mycobacterium tuberculosis infection and are critically dependent on the reorganization of the cytoskeleton. Since CD44 is an adhesion molecule involved in inflammatory responses and is connected to the actin cytoskeleton, we investigated the role of CD44 in both these processes. Macrophage (Mφ) recruitment into M. tuberculosis–infected lungs and delayed-type hypersensitivity sites was impaired in CD44-deficient (CD44–/–) mice. In addition, the number of T lymphocytes and the concentration of the protective key cytokine IFN-γ were reduced in the lungs of infected CD44–/– mice. The production of IFN-γ by splenocytes of CD44–/– mice was profoundly increased upon antigen-specific stimulation. Flow cytometry analysis revealed that soluble CD44 can directly bind to virulent M. tuberculosis. Mycobacteria also interacted with Mφ-associated CD44, as reflected by reduced binding and internalization of bacilli by CD44–/– Mφs. This suggests that CD44 is a receptor on Mφs for binding of M. tuberculosis. CD44–/– mice displayed a decreased survival and an enhanced mycobacterial outgrowth in lungs and liver during pulmonary tuberculosis. In summary, we have identified CD44 as a new Mφ binding site for M. tuberculosis that mediates mycobacterial phagocytosis, Mφ recruitment, and protective immunity against pulmonary tuberculosis.

Authors

Jaklien C. Leemans, Sandrine Florquin, Mirjam Heikens, Steven T. Pals, Ronald van der Neut, Tom van der Poll

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Figure 8

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(a) DTH response in footpads of mice. CD44+/+ (white bar) and CD44–/– (b...
(a) DTH response in footpads of mice. CD44+/+ (white bar) and CD44–/– (black bar) mice were immunized with heat-killed M. tuberculosis and challenged in one hind footpad with PPD and in the other with saline. Footpad swelling was measured 0 and 24 hours after the antigen challenge and calculated as described in Methods. Data are shown as mean ± SEM of five mice. *P < 0.05 vs. control. (b) Representative view of the footpad of a CD44+/+ mouse 48 hours after a DTH reaction, showing a classical picture of a DTH reaction: a demarcated inflammatory infiltrate with slight edema (original magnification, ×50; H&E staining). (c) Histological analysis of the footpad of a CD44–/– mouse demonstrated a dense and diffuse inflammatory infiltrate together with a pronounced edema. (d–g) Immunohistochemical detection of PMNs (d and e) and mononuclear cells (f and g) in DTH footpads showed that the inflammatory infiltrate of CD44–/– mice was mostly composed of PMNs (e; original magnification, ×100), whereas mononuclear cells were the predominant cell type found in CD44+/+ mice (f; original magnification, ×100).