Editors' ChoiceImmunology

Aiding the Invaders?

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Science Signaling  21 Dec 2010:
Vol. 3, Issue 153, pp. ec389
DOI: 10.1126/scisignal.3153ec389

Although it elicits a substantial immune response, Mycobacterium tuberculosis (M. tb, the agent that causes tuberculosis) typically escapes destruction to establish a persistent infection. Raghuvanshi et al. found that a mixed population of splenocytes from infected mice showed decreased proliferation to a T cell mitogen compared with those from uninfected animals, whereas the proliferative responses of isolated CD4+ and CD8+ T cells from infected and uninfected mice were similar. Coculture analyses implicated accessory cells in the inhibition of T cell proliferation, and marker analyses indicated that mesenchymal stem cells (MSCs, an identification confirmed by their ability to differentiate into adipocytes) infiltrated the lungs and spleen of mice infected with M. tb. Indeed, MSC depletion from splenocytes restored T cell proliferation, and T cells from the lymph nodes of infected animals (lymph nodes did not harbor M. tb or show detectable MSC) had normal proliferative responses. Transgenic mice resistant to M. tb were rendered susceptible to infection by infusion of MSCs, and adoptive transfer studies indicated that MSCs converted naive CD4+ T cells toward the Treg lineage. Supernatants of splenocyte cultures from infected mice showed an MSC-dependent increase in nitric oxide (NO, which has been implicated in MSC immunosuppressive activity and also in inhibiting M. tb growth) compared with those from uninfected mice, and pharmacological inhibition of inducible nitric oxide synthase (iNOS) partially restored the T cell proliferative response. Microscopic analysis revealed MSCs surrounding granuloma-like structures containing acid-fast bacilli in the lungs and spleens of infected animals; MSCs from mice lacking iNOS2 showed reduced migration toward granulomas in infected wild-type animals and, unlike MSCs from wild-type mice, were ineffective at inhibiting the proliferation of cocultured T cells. Supernatants of cultures of T cells from M. tb–infected spleens also showed increased concentrations of interferon-γ (IFN-γ, which is produced by activated T cells) compared with those from uninfected mice, and neutralizing antibodies directed against IFN-γ both decreased supernatant NO and enhanced splenocyte proliferation. Patient biopsies confirmed the presence of MSCs in M. tb–infected granulomas, and lymphocytes from these lesions showed attenuated proliferation to a T cell mitogen. The authors conclude that recruited MSCs create an immunosuppressive zone in the vicinity of M. tb—contributing to its ability to establish a persistent infection—and may present a therapeutic target.

S. Raghuvanshi, P. Sharma, S. Singh, L. Van Kaer, G. Das, Mycobacterium tuberculosis evades host immunity by recruiting mesenchymal stem cells. Proc. Natl. Acad. Sci. U.S.A. 107, 21653–21658 (2010). [Abstract] [Full Text]

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