LAG3 Expression in Active Mycobacterium tuberculosis Infections

Abstract

Mycobacterium tuberculosis (MTB) is a highly successful pathogen because of its ability to persist in human lungs for long periods of time. MTB modulates several aspects of the host immune response. Lymphocyte-activation gene 3 (LAG3) is a protein with a high affinity for the CD4 receptor and is expressed mainly by regulatory T cells with immunomodulatory functions. To understand the function of LAG3 during MTB infection, a nonhuman primate model of tuberculosis, which recapitulates key aspects of natural human infection in rhesus macaques (Macaca mulatta), was used. We show that the expression of LAG3 is highly induced in the lungs and particularly in the granulomatous lesions of macaques experimentally infected with MTB. Furthermore, we show that LAG3 expression is not induced in the lungs and lung granulomas of animals exhibiting latent tuberculosis infection. However, simian immunodeficiency virus-induced reactivation of latent tuberculosis infection results in an increased expression of LAG3 in the lungs. This response is not observed in nonhuman primates infected with non-MTB bacterial pathogens, nor with simian immunodeficiency virus alone. Our data show that LAG3 was expressed primarily on CD4(+) T cells, presumably by regulatory T cells but also by natural killer cells. The expression of LAG3 coincides with high bacterial burdens and changes in the host type 1 helper T-cell response.

Host-directed therapies for bacterial and viral infections

“…In vitro treatment with a PD1 mAb of cell cultures derived from patients with TB reduced immunosuppression by blocking T cell apoptosis, restoring IFNγ production and triggering IFNγ-dependent killing of Mtb-infected macrophages 122,123 . Similarly, the increased surface expression of CTLA4 has also been reported in TB 121,126,127 , and the checkpoint receptor LAG3 was found to be highly expressed by CD4 + T cells and NK cells in the lungs of non-human primates that progressed to active TB, but not in animals with LTBI 128 . This observation suggests that changes in LAG3 expression patterns influence disease outcome and Mtb replication.…”

CD4 + T-cell–independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection

“…Reactivators displayed significantly reduced production of granzyme B in the lungs compared with the nonreactivators (Fig. 7 G-I), indicating a correlation between increased granzyme B production, which occurs at least partly within CD8 + T cells (31,32), and increased control of both SIVand TB-associated pathology. Although the majority of cells expressing granzyme B were CD3 + lymphocytes (Fig.…”

“…Blood was drawn 1 or 2 wk before Mtb infection and then weekly thereafter for measuring complete blood count and serum chemistry (22,26). Blood collected in EDTA tubes (Sarstedt AG & Co.) was used for whole-blood flow cytometry using the panels described earlier (14,26,31). BAL samples were obtained, as previously described, 2 wk before Mtb infection, again at 3, 7, 11, and 14 wk (22,26), and then analyzed for CFUs and flow cytometry.…”

“…Flow cytometry was performed on whole blood and BAL samples from all animals, as previously described (14,26,31).…”

Antigen Availability Shapes T Cell Differentiation and Function during Tuberculosis

“…Likewise, in cynomologous macaques, ESAT-6-specific T cells in the blood were capable of producing multiple cytokines, but T cells isolated from lung granulomas produced multiple cytokines only after polyclonal stimulation, but not after stimulation with ESAT-6 peptides (Gideon et al, 2015). Furthermore, in rhesus macaques, LAG3, a cell surface inhibitory receptor associated with CD4 T cell exhaustion in this species (Bosinger et al, 2009; Chew et al, 2016; Fromentin et al, 2016; Rotger et al, 2011), was expressed during TB by lung T cells, but not the blood (Phillips et al, 2015). Thus, antigen-specific T cells may have greater functional capacity in the blood than at the site of high antigenic exposure in the lung.…”