Characterization of Lung γδ T Cells Following Intranasal Infection withMycobacterium bovisBacillus Calmette-Guérin

Abstract

The lungs are considered to have an impaired capacity to contain infection by pathogenic mycobacteria, even in the presence of effective systemic immunity. In an attempt to understand the underlying cellular mechanisms, we characterized the γδ T cell population following intranasal infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG). The peak of γδ T cell expansion at 7 days postinfection preceded the 30 day peak of αβ T cell expansion and bacterial count. The expanded population of γδ T cells in the lungs of BCG-infected mice represents an expansion of the resident Vγ2 T cell subset as well as an influx of Vγ1 and of four different Vδ gene-bearing T cell subsets. The γδ T cells in the lungs of BCG-infected mice secreted IFN-γ following in vitro stimulation with ionomycin and PMA and were cytotoxic against BCG-infected peritoneal macrophages as well as against the uninfected J774 macrophage cell line. The cytotoxicity was selectively blocked by anti-γδ TCR mAb and strontium ions, suggesting a granule-exocytosis killing pathway. Depletion of γδ T cells by injection of specific mAb had no effect on the subsequent developing CD4 T cell response in the lungs of BCG-infected mice, but significantly reduced cytotoxic activity and IFN-γ production by lung CD8 T cells. Thus, γδ T cells in the lungs might help to control mycobacterial infection in the period between innate and classical adaptive immunity and may also play an important regulatory role in the subsequent onset of αβ T lymphocytes.

Early granuloma formation after aerosol Mycobacterium tuberculosis infection is regulated by neutrophils via CXCR3‐signaling chemokines

“…+ˇ+ T cells exhibit regulatory functions in mucosal immune responses [26,31] and, in particular, regulate the focally dense granulomas during M. tuberculosis infection [24]. Elevated PMN influx into the granuloma has been observed in TCRˇ-/-mice, indicating a regulatory interplay between +ˇ+ T cells and PMN.…”

γδ T cells condition dendritic cells in vivo for priming pulmonary CD8 T cell responses against Mycobacterium tuberculosis

“…cd cells are rapidly recruited to the lungs of mice infected intranasally (i.n.) with BCG, and they produce IFN-c following in vitro stimulation and are cytotoxic against BCG-infected macrophages [16]. Evidence from mouse [17] and human [18,19] studies suggests that cd T cells may participate in adaptive immune responses by modulating DC functions [14] or by producing .…”

“…Because of evidence suggestive of reduced CD8 activity in the lungs of cd-depleted mice vaccinated i.n. with BCG [16], and given the important role of CD8 T cells in protection from M. tuberculosis infection [23], the possibility exists that cd T cells recruited early to the lungs regulate the development of late-appearing CD8 T cells and hence influence the degree of protection against M. tuberculosis infection. Furthermore, we reasoned that cd T cells recruited to the site of infection [16] may come into contact with resident DC [24] at a maturation stage corresponding to innate immunity.…”

CD3 expression distinguishes two γδT cell receptor subsets with different phenotype and effector function in tuberculous pleurisy

“…In this context, recent findings suggest strongly the existence of an antigen-presenting molecule different from the currently known major histocompatibility complex (MHC)/CD1 molecules [13,14]. gdT cells are activated in response to Mtb [15,16], and an expansion during mycobacterial infection has been observed in experimental models as well as in secondary challenges with either bacilli Calmette-Guérin (BCG) or virulent Mtb [10,17]. Furthermore, gdT cells from BCG-vaccinated individuals expand upon restimulation with mycobacterial antigens and display a memory-like phenotype [18].…”

“…Vd1 chain expressing gdT cells are a minor subset in blood (10-30% of peripheral gdT cells) [7] that can be activated and expanded in response to lipid extracts of Gramnegative bacteria and polyprenylphosphates [8]. gdT cells display an important number of effector functions leading to proliferation, release of T helper type 1 (Th1) cytokines and cytotoxic activity against pathogen-infected macrophages [9][10][11]. gdT cells recognize non-peptide phosphorylated metabolites of isoprenoid biosynthesis, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) being the most potent antigen described.…”