Research Article: LAG-3 potentiates the survival of Mycobacterium tuberculosis in host phagocytes by modulating mitochondrial signaling in an in-vitro granuloma model

Date Published: September 7, 2017

Publisher: Public Library of Science

Author(s): Bonnie L. Phillips, Uma S. Gautam, Allison N. Bucsan, Taylor W. Foreman, Nadia A. Golden, Tianhua Niu, Deepak Kaushal, Smriti Mehra, Gobardhan Das.


CD4+ T-cell mediated Th1 immune responses are critical for immunity to TB. The immunomodulatory protein, lymphocyte activation gene-3 (LAG-3) decreases Th1-type immune responses in T-cells. LAG-3 expression is significantly induced in the lungs of macaques with active TB and correlates with increased bacterial burden. Overproduction of LAG-3 can greatly diminish responses and could lead to uncontrolled Mtb replication. To assess the effect of LAG-3 on the progression of Mtb infection, we developed a co-culture system wherein blood-derived macrophages are infected with Mtb and supplemented with macaque blood or lung derived CD4+ T-cells. Silencing LAG-3 signaling in macaque lung CD4+ T-cells enhanced killing of Mtb in co-cultures, accompanied by reduced mitochondrial electron transport and increased IFN-γ expression. Thus, LAG-3 may modulate adaptive immunity to Mtb infection by interfering with the mitochondrial apoptosis pathway. Better understanding this pathway could allow us to circumvent immune features that promote disease.

Partial Text

Mtb, the causative agent of TB results in approximately 1.4 million deaths annually [1, 2]. Additionally, 9 million individuals are newly infected with Mtb each year [3]. The interaction between the phagocytes and T-cells within the lung granuloma are key for the control of Mtb. Modulation of the Th1 immune response, which can potentially sterilize infection, is required for control of tissue damaging immunopathology, but may provide the bacillus with a niche to persist [4]. Immunosuppression can modulate T-cell function through a decreased ability to recognize antigen, activate, proliferate, produce cytokines or eventually, increased exhaustion [5–7], potentially resulting in the loss of containment of Mtb [8, 9].

The Tulane National Primate Research Center Institutional Animal Care and Use Committee (IACUC) and the Tulane Institutional Biosafety Committee (IBC) approved all procedures.

Mtb owes is pathogenic success to its remarkably different strategy of interacting with its human host, with which it has co-evolved [4]. Thus, while most pathogens attempt to mask their immunogenicity, Mtb is rather unique in being able to elicit extremely high immune responses, as exemplified by the use of BCG as an adjuvant4. This is counterintuitive and Mtb appears to have evolved to retain and promote its immunogenicity. This is crucial in order to generate the classical tissue damage associated with TB—which is itself necessary for the transmission of Mtb. However, in order to complete this cycle, Mtb must first successfully persist in the wake of strong immune responses it elicits. Several lines of evidence indicate that Mtb successfully modulates host innate and adaptive immune responses [60]. Furthermore, IFN-γ is critical for the control of Mtb, which interferes with IFN-γ signaling at several steps [61, 62].




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