In cancer and chronic infectious diseases, immune checkpoint-blockade of inhibitory receptors can enhance T-cell immunity. In tuberculosis (TB), a chronic infectious disease, prolonged antigen... Show moreIn cancer and chronic infectious diseases, immune checkpoint-blockade of inhibitory receptors can enhance T-cell immunity. In tuberculosis (TB), a chronic infectious disease, prolonged antigen exposure can potentially drive terminal T-cell differentiation towards functional 'exhaustion': in human TB T-cells express PD-1 (programmed cell death protein-1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein-4). However, in murine TB not PD-1 but rather killer cell lectin-like receptor subfamily-G1 (KLRG1) was a superior indicator of terminal T-cell differentiation. We therefore compared expression of KLRG1, PD-1 and CTLA-4 on T-cells in different stages of human TB, and also analysed their induction following BCG-vaccination. KLRG1, PD-1 and CTLA-4-expression were highest on in vitro BCG-stimulated CD4(+) T-cells following recent TB-treatment; KLRG1 and PD-1-expression on CD4(+) T-cells in active - but not latent TB were only slightly increased compared to healthy donors. BCG-vaccination induced KLRG1-expression on BCG-stimulated CD8(+) but not CD4(+) T-cells, while neither PD-1 nor CTLA-4-expression increased. KLRG1-expressing CD8(+) T-cells exhibited markedly decreased proliferation, whereas PD-1(+) T-cells proliferated after in vitro BCG-stimulation. Thus, we demonstrate the presence of increased KLRG1-expressing T-cells in TB-treated individuals, and present KLRG1 as a marker of decreased human T-cell proliferation following BCG-vaccination. These results expand our understanding of cell-mediated immune control of mycobacterial infections. (c) 2015 Elsevier Ltd. All rights reserved. Show less
Mycobacterium bovis bacillus Calmette-Guérin (M. bovis BCG), the only currently available vaccine against tuberculosis, induces variable protection in adults. Immune correlates of protection are... Show moreMycobacterium bovis bacillus Calmette-Guérin (M. bovis BCG), the only currently available vaccine against tuberculosis, induces variable protection in adults. Immune correlates of protection are lacking, and analyses on cytokine-producing T-cell subsets in protected vs. non-protected cohorts have yielded inconsistent results. We studied the primary T-cell response, both pro-inflammatory and regulatory T-cell responses, induced by BCG-vaccination in adults. Twelve healthy adult volunteers, who were Tuberculin skin test (TST) -negative, QuantiFERON test (QFT) -negative, and BCG-naïve, were vaccinated with BCG and followed-up prospectively. BCG-vaccination induced an unexpectedly dichotomous immune response in this small, BCG-naive young adult cohort: BCG-vaccination induced either IFNγ+IL2+TNFa+ polyfunctional CD4+ T-cells concurrent with CD4+IL17A+ and CD8+IFNγ+ T-cells, or, in contrast, virtually absent cytokine responses with induction of CD8+ regulatory T-cells. Significant induction of polyfunctional CD4+IFNγ+IL2+TNFa+ T-cells and IFNγ production by PBMCs was confined to individuals with strong immunization-induced local skin inflammation and increased serum C-reactive protein (CRP). Conversely, in individuals with mild inflammation, regulatory-like CD8+ T-cells were uniquely induced. Thus, BCG-vaccination either induced a broad pro-inflammatory T-cell response with local inflammatory reactogenicity, or in contrast a predominant CD8+ regulatory T-cell response with mild local inflammation, poor cytokine induction and absent polyfunctional CD4+ T-cells. Further detailed fine mapping of the heterogeneous host response to BCG-vaccination using classical and non-classical immune markers will enhance our understanding of the mechanisms and determinants that underlie the induction of apparently opposite immune responses, and how these impact on BCGs ability to induce protective immunity to TB. Show less
Regulatory T (Treg) cells can balance normal tissue homeostasis by limiting inflammatory tissue damage, e.g. during pathogen infection, but on the other hand can also limit protective immunity... Show moreRegulatory T (Treg) cells can balance normal tissue homeostasis by limiting inflammatory tissue damage, e.g. during pathogen infection, but on the other hand can also limit protective immunity induced during natural infection or following vaccination. Because most studies have focused on the role of CD4(+) Treg cells, relatively little is known about the phenotype and function of CD8(+) Treg cells, particularly in infectious diseases. Here, we describe for the first time the expression of CD39 (E-NTPDase1) on Mycobacterium-activated human CD8(+) T cells. These CD8(+) CD39(+) T cells significantly co-expressed the Treg markers CD25, Foxp3, lymphocyte activation gene-3 (LAG-3), and CC chemokine ligand 4 (CCL4), and suppressed the proliferative response of antigen-specific CD4(+) T helper-1 (Th1) cells. Pharmacological or antibody mediated blocking of CD39 function resulted in partial reversal of suppression. These data identify CD39 as a novel marker of human regulatory CD8(+) T cells and indicate that CD39 is functionally involved in suppression by CD8(+) Treg cells. Show less
