CCL5 participates in early protection against Mycobacterium tuberculosis

Abstract

Control of M.tb, the causative agent of TB, requires immune cell recruitment to form lung granulomas. The chemokines and chemokine receptors that promote cell migration for granuloma formation, however, are not defined completely. As immunity to M.tb manifests slowly in the lungs, a better understanding of specific roles for chemokines, in particular those that promote M.tb-protective T(H)1 responses, may identify targets that could accelerate granuloma formation. The chemokine CCL5 has been detected in patients with TB and implicated in control of M.tb infection. To define a role for CCL5 in vivo during M.tb infection, CCL5 KO mice were infected with a low dose of aerosolized M.tb. During early M.tb infection, CCL5 KO mice localized fewer APCs and chemokine receptor-positive T cells to the lungs and had microscopic evidence of altered cell trafficking to M.tb granulomas. Early acquired immunity and granuloma function were transiently impaired when CCL5 was absent, evident by delayed IFN-gamma responses and poor control of M.tb growth. Lung cells from M.tb-infected CCL5 KO mice eventually reached or exceeded the levels of WT mice, likely as a result of partial compensation by the CCL5-related ligand, CCL4, and not because of CCL3. Finally, our results suggest that most T cells use CCR5 but not CCR1 to interact with these ligands. Overall, these results contribute to a model of M.tb granuloma formation dependent on temporal regulation of chemokines rather than on redundant or promiscuous interactions.

Lysosomal phospholipase A2: A novel player in host immunity to Mycobacterium tuberculosis

“…Our data suggest that LPLA 2 deficiency impairs early dissemination of mycobacteria to the spleen but not to the lung draining mLNs. However, while the absence of LPLA 2 did not affect mycobacterial loads in the mLNs, it significantly reduced the production of TNF-α and CCL5, both of which contribute to early protection against M. tuberculosis infection [23,24]. As activated macrophages are the main TNF-α producers, diminished production of this cytokine indicates that LPLA 2 deficient macrophages are not fully activated in vivo.…”

Innate Immune Gene Polymorphisms in Tuberculosis

“…M. tuberculosis infection of human alveolar macrophages induces the production of RANTES, which reduces intracellular bacterial growth (194). The role of RANTES in protective immunity to M. tuberculosis infection has also been reported in mouse macrophages (191) and in knockout mice (252).…”

“…RANTES (regulated upon activation, normal T-cell expressed, and secreted), a member of the C-C chemokine subfamily, acts as a chemokine for T cells, monocytes/macrophages, eosinophils, and basophils. RANTES promotes granuloma formation in M. tuberculosis-infected lungs in a mouse model (44,252). M. tuberculosis infection of human alveolar macrophages induces the production of RANTES, which reduces intracellular bacterial growth (194).…”

Killer Cell Lectin-Like Receptor G1 Deficiency Significantly Enhances Survival after Mycobacterium tuberculosis Infection

“…Cytokines were stained following a 4-h incubation with 10 g/ml anti-CD3 (145-2C11) and 1 g/ml anti-CD28 (37.51) in the presence of GolgiStop or concanavalin A (ConA; Sigma) (10 g/ml) and GolgiStop. Mice were injected with bromodeoxyuridine (BrdU) 24 h prior to necropsy, and intracellular BrdU was quantified using a BD fluorescein isothiocyanate (FITC) BrdU kit (BD Biosciences) as described previously (19). Samples were read using an LSRII flow cytometer and analyzed with FACSDiva software (BD Biosciences).…”