TCR Repertoire, Clonal Dominance, and Pulmonary Trafficking of Mycobacterium-Specific CD4+ and CD8+ T Effector Cells in Immunity Against Tuberculosis

Abstract

Clonal responses of Mycobacterium tuberculosis-specific CD4+ or CD8+ T effector cells producing antituberculosis cytokine IFN-γ in the context of immune protection against tuberculosis remain poorly characterized in humans. Utilizing decade-long TCR expertise, we previously developed a useful method to isolate clonotypic TCR sequences from Ag-specific IFN-γ–producing T cells and to specifically measure clonotypic TCR frequencies in the T cell pool. In this study, we investigated TCR Vβ repertoires/CDR3 usage, clonal expansion or dominance, and pulmonary trafficking or accumulation for purified protein deritative (PPD)-specific T effector cells producing IFN-γ during bacillus Calmette-Guérin (BCG) vaccination and subsequent M. tuberculosis challenge of macaques. We found that while PPD-specific CD4+ and CD8+ T effector clones employed diverse TCR Vβ repertoires, 30–33% of IFN-γ+CD4+ T cell clones from three M. tuberculosis-infected macaques expressed TCR bearing a conserved residue leucine in CDR3. Many Ag-specific IFN-γ+ CD4+ and few CD8+ T effector cells emerged as dominant clones during mycobacterial infections and underwent major recall expansion after pulmonary M. tuberculosis infection of BCG-vaccinated macaques. PPD-specific T cell clones readily trafficked to the airway or lung after BCG vaccination or M. tuberculosis infection, and some of them continuously accumulated in lungs during M. tuberculosis infection even after they became undetectable in the circulation. Importantly, remarkable recall expansion and pulmonary accumulation of T effector cells coincided with BCG-induced protection against tuberculosis. Thus, rapid clonal expansion and pulmonary accumulation of Ag-specific T effector cells appear to be one of the immune mechanisms underlying immunity against tuberculosis.

Phosphoantigen/IL2 Expansion and Differentiation of Vγ2Vδ2 T Cells Increase Resistance to Tuberculosis in Nonhuman Primates

“…In fact, frequencies of pulmonary CD4+ and CD8+ Th1-like cells in Picostim/IL2 group are significantly higher than those in saline/BSA or IL2 alone control during primary Mtb infection. The reason why enhanced responses were seen prominent only in pulmonary compartment but not in blood may be due to the fact that pulmonary Mtb infection leads to dominance of immune responses in lung but not in peripheral blood [40]. These results suggest that phosphoantigen expansion of Vγ2Vδ2 T effector cells may serve as immune adjuvant enhancing CD4+ and CD8+ Th1 responses.…”

“…Shown on left are real time quantitative PCR data for mRNA expression levels of perforin and granulysin expressed by macaque Vγ2Vδ2 T effector cells capable of restricting intracellular Mtb growth. The quantitation was done using the methods as we previously described [40]. Data are means with SEM from phosphoantigen-activated Vγ2Vδ2 T effector cells from 3 Mtb-infected macaques in 2 independent experiments.…”

“…In fact, Mtb infection or BCG vaccination can induce remarkable expansion of Vγ2Vδ2 T cells at ∼3–4 weeks postinfection, and rapid recall expansion of Vγ2Vδ2 T cells in BCG-vaccinated macaques correlates with the vaccine-induced protection against life-threatening TB [9]. Earlier and greater-magnitude expansion of Vγ2Vδ2 T cells during Mtb infection appears to create a proof-of-concept setting in which to examine immune function of Mtb-specific Vγ2Vδ2 T effector cells in primates, as rapid clonal expansion and pulmonary trafficking of Mtb-specific CD4+/CD8+ T cells have been interpreted as important immune events in immunity against TB in macaques [40]. The resistance to TB after phosphoantigen treatment could be due to killing and blunting of Mtb as they enter the pulmonary compartment after infection, since the treatment is given during early Mtb infection rather than established TB disease.…”

Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: Immunity interruptus

“…While we are far from being able to test such hypotheses, new studies highlight the value of studying TCRs used by M. tuberculosis specific T cells. Du et al identified TCRβ sequences from PPD-reactive CD4 + and CD8 + T cells from BCG vaccinated macaques [61]. While these sequences were diverse, when challenged with M. tuberculosis , several but not all TCRβs underwent dramatic clonal expansion.…”

Clonal Immune Responses of Mycobacterium-Specific γδ T Cells in Tuberculous and Non-Tuberculous Tissues during M. tuberculosis Infection

“…IFNγ has been shown to play a role in protection against active Mtb infection in mice [5]. While human studies have not found a correlation between blood IFNγ and protection against TB, our recent mechanistic studies suggest that rapid pulmonary trafficking of mycobacterium-specific CD4+ and CD8+ T effector cells producing IFNγ appears to be one of the mechanisms underlying BCG vaccine-induced immunity against primary TB [9].…”