Transient role of CD4+CD25+ regulatory T cells in mycobacterial infection in mice

Abstract

CD4(+)CD25(+) regulatory T (Treg) cells cause immune suppression by inhibiting T cell effector functions and play pivotal roles not only in self-tolerance but also in immune response to parasitic microbial pathogens. Mycobacteria are major parasitic bacterial pathogens, but the role of CD4(+)CD25(+) Treg cells in mycobacterial infection is not yet defined. In this study we found that, at the early stage of infection, depletion of CD25(+) cells reduced both bacterial load and granuloma formation in mice infected with Mycobacterium tuberculosis strains, such as M. tuberculosis Erdman or M. tuberculosis Kurono. However, at a later stage of infection, bacterial burden and histopathology were similar regardless of depletion of CD25(+) cells. Severe combined immunodeficient (SCID) mice reconstituted with CD4(+)CD25(-) T cells alone or a combination of CD4(+)CD25(+) and CD4(+)CD25(-) T cells showed similar bacterial loads and survival kinetics after infection with M. tuberculosis Erdman. Consistent with in vivo data, in vitro studies revealed that mycobacterial antigens, purified protein derivative of tuberculin (PPD), failed to induce the suppressive function of CD4(+)CD25(+) Treg cells to CD4(+)CD25(-) effector T cells, as demonstrated by the lack of response of CD4(+)CD25(+) T cells to PPD, in mice chronically infected with Mycobacterium bovis bacillus Calmette-Guérin and M. tuberculosis. Our data show that CD4(+)CD25(+) Treg cells have a transient effect at the early stage of mycobacterial infection but, contrary to the expectation, have little impact on the overall course of infection.

Latent Tuberculosis Infection: Myths, Models, and Molecular Mechanisms

“…Consistent with this hypothesis, ex vivo depletion of CD4 ϩ CD25 ϩ cells from peripheral blood mononuclear cells (PBMCs) resulted in increased numbers of M. tuberculosis antigen-specific IFN-␥-producing T cells in seven of eight patients with active TB (199). Depletion of CD25 ϩ cells re-duced lung and spleen bacillary loads and granuloma formation in M. tuberculosis-infected mice during acute infection but not during the later stage of infection (202). The precise role of B cells in controlling TB infection remains to be determined.…”

Multicolor Flow Cytometric Analyses of CD4+ T Cell Responses to Mycobacterium tuberculosis-Related Latent Antigens

“…This result may be due to the migration of IL-10-producing T cells from the blood to local inflammatory sites. Alternatively, M. tuberculosis-specific IL-10-producing T cells may have a transient role during early infection and self-antigen-specific IL-10-producing T cells may contribute to halting inflammation (37). The candidate of self-antigen is a dump of M. tuberculosis granuloma.…”

CD4+T Cells: Guardians of the Phagosome

“…The TCR specificity of these cells is unclear, however, since M. tuberculosis p:MHCII-specific regulatory T cells are lost at later times after infection (114). In addition, the relevance of regulatory T cells in granulomas is uncertain, since late depletion of regulatory T cells had no effect on the number of M. tuberculosis organisms in this location (195).…”