The Tim3–Galectin 9 Pathway Induces Antibacterial Activity in Human Macrophages Infected with <i>Mycobacterium tuberculosis</i>

Sada‐Ovalle, Isabel; Chávez‐Galán, Leslie; Torre-Bouscoulet, Luis; Nava-Gamiño, Lourdes; Barrera, Lourdes; Jayaraman, Pushpa; Torres, Martha; Salazar-Lezama, Miguel Ángel; Behar, Samuel M.

doi:10.4049/jimmunol.1200990

Cited by 81 publications

(65 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inhibition of Gal-9 Binding to TIM-3 Inhibited Reconstitution and Self-Renewal of Human AML LSCs in a Xenogeneic Transplantation Model To test whether the putative TIM-3/Gal-9 autocrine signaling is critical for function of LSCs, we blocked serum Gal-9 to bind to surface TIM-3 by utilizing a neutralizing Gal-9 antibody (9M1-3) (Klibi et al, 2009;Sada-Ovalle et al, 2012) in xenogeneic hosts. Purified CD34 + cells from four AML cases (patients 2, 14, 26, and 28) were transplanted into irradiated NSG mice.…”

Section: Resultsmentioning

confidence: 99%

A TIM-3/Gal-9 Autocrine Stimulatory Loop Drives Self-Renewal of Human Myeloid Leukemia Stem Cells and Leukemic Progression

et al. 2015

View full text Add to dashboard Cite

Signaling mechanisms underlying self-renewal of leukemic stem cells (LSCs) are poorly understood, and identifying pathways specifically active in LSCs could provide opportunities for therapeutic intervention. T-cell immunoglobin mucin-3 (TIM-3) is expressed on the surface of LSCs in many types of human acute myeloid leukemia (AML), but not on hematopoietic stem cells (HSCs). Here, we show that TIM-3 and its ligand, galectin-9 (Gal-9), constitute an autocrine loop critical for LSC self-renewal and development of human AML. Serum Gal-9 levels were significantly elevated in AML patients and in mice xenografted with primary human AML samples, and neutralization of Gal-9 inhibited xenogeneic reconstitution of human AML. Gal-9-mediated stimulation of TIM-3 co-activated NF-κB and β-catenin signaling, pathways known to promote LSC self-renewal. These changes were further associated with leukemic transformation of a variety of pre-leukemic disorders and together highlight that targeting the TIM-3/Gal-9 autocrine loop could be a useful strategy for treating myeloid leukemias.

show abstract

Section: Resultsmentioning

confidence: 99%

A TIM-3/Gal-9 Autocrine Stimulatory Loop Drives Self-Renewal of Human Myeloid Leukemia Stem Cells and Leukemic Progression

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Mice lacking IL-1β, a pro-inflammatory cytokine produced by macrophages, or its receptor are highly susceptible to M. tuberculosis infection and IL-1β directly inhibits intracellular growth of M. tuberculosis 47, 52, 70-72 . Although mice lacking IL-1β die prematurely from infection, IL-1β can also be detrimental by recruiting pathogenic Th17 cells and neutrophils to the lung, resulting in tissue inflammation 46, 73, 74 .…”

Section: Reassessing Protective Immunitymentioning

confidence: 99%

In search of a new paradigm for protective immunity to TB

et al. 2014

Self Cite

View full text Add to dashboard Cite

“…That finding was the result of the limited pro-inflammatory cytokine production [12]. Given that Tim-3 expression has been associated with a T cell-exhausted phenotype, we hypothesized that by blocking Tim-3 in HIV+ patients we could improve the ability of macrophages and T cells to restrict bacterial replication.…”

Section: Resultsmentioning

confidence: 99%

“…Upon Gal9 blocking, we observed restriction of bacterial growth; however, it was less dramatic than the result observed with Tim-3 (Figure 5b). In contrast, when the control group was analysed, more CFU were counted in the condition in which blocking antibodies were added [12]. To determine whether the double-blocking of Tim-3 and PD-1 increased control of bacterial growth, T cells were treated with anti-Tim-3 plus anti-PD-1 blocking antibodies.…”

Section: Resultsmentioning

confidence: 99%

Tim‐3 blocking rescue macrophage and T cell function against Mycobacterium tuberculosis infection in HIV+ patients

Sada‐Ovalle

Ocaña-Guzmán

Pérez-Patrigeón

et al. 2015

Journal of the International AIDS Society

Self Cite

View full text Add to dashboard Cite

IntroductionT cell immunoglobulin and mucin domain (Tim) 3 and programmed death 1 (PD-1) are co-inhibitory receptors involved in the so-called T cell exhaustion, and in vivo blockade of these molecules restores T cell dysfunction. High expression of Tim-3 and PD-1 is induced after chronic antigen-specific stimulation of T cells during HIV infection. We have previously demonstrated that the interaction of Tim-3 with its ligand galectin-9 induces macrophage activation and killing of Mycobacterium tuberculosis. Our aim in this study was to analyze the Tim-3 expression profile before and after six months of antiretroviral therapy and the impact of Tim-3 and PD-1 blocking on immunity against M. tuberculosis.Materials and methodsHIV+ patients naïve to anti-retroviral therapy (ART) were followed up for six months. Peripheral immune-cell phenotype (CD38/HLA-DR/galectin-9/Tim-3 and PD-1) was assessed by flow cytometry. Supernatants were analyzed with a multiplex cytokine detection system (human Th1/Th2 cytokine Cytometric Bead Array) by flow cytometry. Control of bacterial growth was evaluated by using an in vitro experimental model in which virulent M. tuberculosis-infected macrophages were cultured with T cells in the presence or absence of Tim-3 and PD-1 blocking antibodies. Interleukin-1 beta treatment of infected macrophages was evaluated by enumerating colony-forming units.ResultsWe showed that HIV+ patients had an increased expression of Tim-3 in T cells and were able to control bacterial growth before ART administration. By blocking Tim-3 and PD-1, macrophages and T cells recovered their functionality and had a higher ability to control bacterial growth; this result was partially dependent on the restitution of cytokine production.ConclusionsIn this study, we demonstrated that increased Tim-3 expression can limit the ability of the immune system to control the infection of intracellular bacteria such as M. tuberculosis. The use of ART and the in vitro manipulation of the Tim-3 and PD-1 molecules restored the functionality of T cells and macrophages to restrict bacterial growth. Our results provide a novel immune strategy that may be implemented in the near future in order to improve the immune responses in HIV+ patients.

show abstract

The Tim3–Galectin 9 Pathway Induces Antibacterial Activity in Human Macrophages Infected with Mycobacterium tuberculosis

Cited by 81 publications

References 33 publications

A TIM-3/Gal-9 Autocrine Stimulatory Loop Drives Self-Renewal of Human Myeloid Leukemia Stem Cells and Leukemic Progression

A TIM-3/Gal-9 Autocrine Stimulatory Loop Drives Self-Renewal of Human Myeloid Leukemia Stem Cells and Leukemic Progression

In search of a new paradigm for protective immunity to TB

Tim‐3 blocking rescue macrophage and T cell function against Mycobacterium tuberculosis infection in HIV+ patients

Contact Info

Product

Resources

About