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Mannose-capped lipoarabinomannan from Mycobacterium tuberculosis preferentially inhibits sphingosine-1-phosphate-induced migration of Th1 cells.

ABSTRACT: Chemokine receptor cross-desensitization provides an important mechanism to regulate immune cell recruitment at sites of inflammation. We previously reported that the mycobacterial cell wall glycophospholipid mannose-capped lipoarabinomannan (ManLAM) could induce human peripheral blood T cell chemotaxis. Therefore, we examined the ability of ManLAM to desensitize T cells to other chemoattractants as a potential mechanism for impaired T cell homing and delayed lung recruitment during mycobacterial infection. We found that ManLAM pretreatment inhibited in vitro migration of naive human or mouse T cells to the lymph node egress signal sphingosine-1-phosphate (S1P). Intratracheal administration of ManLAM in mice resulted in significant increases in T cells, primarily CCR5(+) (Th1) cells, in lung-draining lymph nodes. To investigate the selective CCR5 effect, mouse T cells were differentiated into Th1 or Th2 populations in vitro, and their ability to migrate to S1P with or without ManLAM pretreatment was analyzed. ManLAM pretreatment of Th1 populations inhibited S1P-induced migration but had no effect on Th2 cell S1P-directed migration, suggesting a differential effect by S1P on the two subsets. The PI3K/AKT inhibitor Ly294002 inhibited S1P-directed migration by Th1 cells, whereas the ERK inhibitor U0126 inhibited Th2 cell S1P-directed migration. These observations demonstrate that S1P-induced migratory responses in Th1 and Th2 lymphocytes occurs via different signaling pathways and suggests further that the production of ManLAM during Mycobacterium tuberculosis infection may function to sequester Th1 cells in lung-draining lymph nodes, thereby delaying their recruitment to the lung.

SUBMITTER: Richmond JM

PROVIDER: S-EPMC3518657 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Mannose-capped lipoarabinomannan from Mycobacterium tuberculosis preferentially inhibits sphingosine-1-phosphate-induced migration of Th1 cells.

Richmond Jillian M JM Lee Jinhee J Green Daniel S DS Kornfeld Hardy H Cruikshank William W WW

Journal of immunology (Baltimore, Md. : 1950) 20121105 12

Chemokine receptor cross-desensitization provides an important mechanism to regulate immune cell recruitment at sites of inflammation. We previously reported that the mycobacterial cell wall glycophospholipid mannose-capped lipoarabinomannan (ManLAM) could induce human peripheral blood T cell chemotaxis. Therefore, we examined the ability of ManLAM to desensitize T cells to other chemoattractants as a potential mechanism for impaired T cell homing and delayed lung recruitment during mycobacteria ...[more]

PMID: 23129756

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Project description:CD4+ T cells have a central role in controlling Mtb infection (1). Despite immune control, Mtb persists by interfering with macrophage and T cell function, allowing for pathogen survival. Our group has demonstrated direct and indirect inhibition of CD4+ T cell activation by different Mtb molecules including lipoproteins LpqH, LprA and LprG, and ManLAM (2-5). ManLAM is an abundant glycolipid in the Mtb cell wall and interferes with TCR signaling by down-regulating phosphorylation of Lck, CD3, ZAP70 and LAT (6). Activation through the TCR-CD3 complex leads to marked changes in the proteome of T cells. Entry into cell cycle, production of cytokines and differentiation from naïve to effector and memory T cell are all reflected in the production and modification of multiple proteins. Mass spectrometry (MS) has been used to characterize TCR complex formation (7-11) and the effect of a range of stressors on the T cell proteome (12-14). Recent advances have overcome technical issues in quantitative MS and allow analysis of the complexity and dynamic range of the cellular proteome (15). To extract biological meaning different bioinformatic tools have been developed for MS based cellular studies (16, 17). In this study we used label-free quantitative MS to characterize the effect of ManLAM on the proteome of activated CD4+ T cells. Approximately 5000 peptides were identified and quantitated from three biological experimental datasets in primary murine CD4+ T cells treated with or without ManLAM and activated with anti-CD3 and anti-CD28 monoclonal antibodies (mAb). Peptides with varying abundance were selected by likelihood ratio based statistical significance by comparing the intensities under different experimental conditions. ManLAM treatment resulted in abundance changes for 149 peptides representing 131 proteins in the activated CD4+ T cell proteome that affected a variety of enriched cluster modules and pathways. Validation experiments confirmed Man LAM induced inhibition of Proliferating Cell Nuclear Antigen (PCNA) that regulates cell cycle progression. Protein-protein interaction (PPI) network analysis revealed a central role for the Akt/mTOR signaling pathway. WB studies revealed decreased phosphorylation of both Akt and mTOR in ManLAM treated CD4+ T cells as well as decreased expression of Otub1, a key molecule regulated by mTOR. Thus disruption of the activated CD4+ T cell proteome by ManLAM-mediated inhibition of proximal TCR signaling is primarily mediated through inhibition of Akt-mTOR signaling.

Dataset Information

Mannose-capped lipoarabinomannan from Mycobacterium tuberculosis preferentially inhibits sphingosine-1-phosphate-induced migration of Th1 cells.

Publications

Mannose-capped lipoarabinomannan from Mycobacterium tuberculosis preferentially inhibits sphingosine-1-phosphate-induced migration of Th1 cells.

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