Host resistance to pulmonary <i>Mycobacterium tuberculosis</i> infection requires CD153 expression. Sallin, M. A, Kauffman, K. D, Riou, C., Du Bruyn, E., Foreman, T. W, Sakai, S., Hoft, S. G, Myers, T. G, Gardina, P. J, Sher, A., Moore, R., Wilder-Kofie, T., Moore, I. N, Sette, A., Lindestam Arlehamn, C. S, Wilkinson, R. J, & Barber, D. L Nature Microbiology, 3(11):1198–1205, Nature Publishing Group, 2018.
Host resistance to pulmonary <i>Mycobacterium tuberculosis</i> infection requires CD153 expression [link]Paper  doi  abstract   bibtex   
Mycobacterium tuberculosis infection (Mtb) is the leading cause of death due to a single infectious agent and is among the top ten causes of all human deaths worldwide 1. CD4 T cells are essential for resistance to Mtb infection, and for decades it has been thought that IFN$γ$ production is the primary mechanism of CD4 T-cell-mediated protection 2,3. However, IFN$γ$ responses do not correlate with host protection, and several reports demonstrate that additional anti-tuberculosis CD4 T-cell effector functions remain unaccounted for 4-8. Here we show that the tumour-necrosis factor (TNF) superfamily molecule CD153 (encoded by the gene Tnfsf8) is required for control of pulmonary Mtb infection by CD4 T cells. In Mtb-infected mice, CD153 expression is highest on Mtb-specific T helper 1 (T H 1) cells in the lung tissue parenchyma, but its induction does not require T H 1 cell polarization. CD153-deficient mice develop high pulmonary bacterial loads and succumb early to Mtb infection. Reconstitution of T-cell-deficient hosts with either Tnfsf8 −/− or Ifng −/− CD4 T cells alone fails to rescue mice from early mortality, but reconstitution with a mixture of Tnfsf8 −/− and Ifng −/− CD4 T cells provides similar protection as wild-type T cells. In Mtb-infected non-human primates, CD153 expression is much higher on Ag-specific CD4 T cells in the airways compared to blood, and the frequency of Mtb-specific CD153-expressing CD4 T cells inversely correlates with bacterial loads in granulomas. In Mtb-infected humans, CD153 defines a subset of highly polyfunctional Mtb-specific CD4 T cells that are much more abundant in individuals with controlled latent Mtb infection compared to those with active tuberculosis. In all three species, Mtb-specific CD8 T cells did not upregulate CD153 following peptide stimulation. Thus, CD153 is a major immune mediator of host protection against pulmonary Mtb infection and CD4 T cells are one important source of this molecule. Our prior studies showed that IFN$γ$ alone could not account for all CD4 T-cell-mediated protection against pulmonary Mtb infection in mice, so we sought to identify immune mechanisms of protection against Mtb infection. We and others have previously shown that KLRG1 − CX3CR1 − effector CD4 T cells are able to migrate into the lung parenchyma and adoptively transfer protection against Mtb infection, whereas terminally differentiated KLRG1 + CX3CR1 + CD4 T cells accumulate in the lung blood vasculature and do not protect 9-11. To identify molecules selectively associated with host-protective CD4 T cells, we compared the gene expression pattern of CD44 high Foxp3-GFP − lung effector cells from Mtb-infected mice that were separated through fluores-cence-activated cell sorting (FACS) into four populations based on KLRG1 expression and intravascular localization (Fig. 1a). CD44 low Foxp3-GFP − naive T cells purified from the lung paren-chyma and vasculature served as respective controls. We hypothesized that genes of interest would be significantly upregulated in the most abundant and highly protective effector subset (that is, lung parenchymal CD45 intravascular stain negative (CD45iv −) and KLRG1 − cells) compared to both naive T cells and the most abundant non-protective subset (that is, CD45 intravascular stain positive (CD45iv +) and KLRG1 + cells). We identified 211 genes with statistically significant expression differences by both these pairwise comparisons (Fig. 1b). Gene ontology (GO) enrichment analysis found that TNF and TNF receptor (TNFR) superfamily members accounted for \textgreater 5% of all microarray probes for genes with high expression in protective effector CD4 T cells, corresponding to a ̃16-fold enrichment compared to the frequency of this class among all genes measured on the microarray (Fisher's Exact test P \textless 0.0001). Because TNF(R) superfamily molecules are potent mediators of inflammatory responses, we focused on the expression patterns of TNF(R) superfamily molecules across all six populations of T cells and identified genes for which the expression was significantly different for any comparison. KLRG1 − parenchy-mal effectors and KLRG1 + intravascular effectors showed different patterns of expression of these TNF(R) superfamily molecules (Fig. 1b,c), with the majority being expressed to a much greater extent in parenchymal effector CD4 T cells. Tnfsf5 (which encodes CD40L) 12 , Tnfsf14 (which encodes LIGHT) 13 , Lta (which encodes LT$α$) 14 and Tnfrsf9 and Tnfsf9 (which encode 4-1BB and 4-1BB ligand, respectively) 15 were all
@article{Sallin2018,
abstract = {Mycobacterium tuberculosis infection (Mtb) is the leading cause of death due to a single infectious agent and is among the top ten causes of all human deaths worldwide 1. CD4 T cells are essential for resistance to Mtb infection, and for decades it has been thought that IFN$\gamma$ production is the primary mechanism of CD4 T-cell-mediated protection 2,3. However, IFN$\gamma$ responses do not correlate with host protection, and several reports demonstrate that additional anti-tuberculosis CD4 T-cell effector functions remain unaccounted for 4-8. Here we show that the tumour-necrosis factor (TNF) superfamily molecule CD153 (encoded by the gene Tnfsf8) is required for control of pulmonary Mtb infection by CD4 T cells. In Mtb-infected mice, CD153 expression is highest on Mtb-specific T helper 1 (T H 1) cells in the lung tissue parenchyma, but its induction does not require T H 1 cell polarization. CD153-deficient mice develop high pulmonary bacterial loads and succumb early to Mtb infection. Reconstitution of T-cell-deficient hosts with either Tnfsf8 −/− or Ifng −/− CD4 T cells alone fails to rescue mice from early mortality, but reconstitution with a mixture of Tnfsf8 −/− and Ifng −/− CD4 T cells provides similar protection as wild-type T cells. In Mtb-infected non-human primates, CD153 expression is much higher on Ag-specific CD4 T cells in the airways compared to blood, and the frequency of Mtb-specific CD153-expressing CD4 T cells inversely correlates with bacterial loads in granulomas. In Mtb-infected humans, CD153 defines a subset of highly polyfunctional Mtb-specific CD4 T cells that are much more abundant in individuals with controlled latent Mtb infection compared to those with active tuberculosis. In all three species, Mtb-specific CD8 T cells did not upregulate CD153 following peptide stimulation. Thus, CD153 is a major immune mediator of host protection against pulmonary Mtb infection and CD4 T cells are one important source of this molecule. Our prior studies showed that IFN$\gamma$ alone could not account for all CD4 T-cell-mediated protection against pulmonary Mtb infection in mice, so we sought to identify immune mechanisms of protection against Mtb infection. We and others have previously shown that KLRG1 − CX3CR1 − effector CD4 T cells are able to migrate into the lung parenchyma and adoptively transfer protection against Mtb infection, whereas terminally differentiated KLRG1 + CX3CR1 + CD4 T cells accumulate in the lung blood vasculature and do not protect 9-11. To identify molecules selectively associated with host-protective CD4 T cells, we compared the gene expression pattern of CD44 high Foxp3-GFP − lung effector cells from Mtb-infected mice that were separated through fluores-cence-activated cell sorting (FACS) into four populations based on KLRG1 expression and intravascular localization (Fig. 1a). CD44 low Foxp3-GFP − naive T cells purified from the lung paren-chyma and vasculature served as respective controls. We hypothesized that genes of interest would be significantly upregulated in the most abundant and highly protective effector subset (that is, lung parenchymal CD45 intravascular stain negative (CD45iv −) and KLRG1 − cells) compared to both naive T cells and the most abundant non-protective subset (that is, CD45 intravascular stain positive (CD45iv +) and KLRG1 + cells). We identified 211 genes with statistically significant expression differences by both these pairwise comparisons (Fig. 1b). Gene ontology (GO) enrichment analysis found that TNF and TNF receptor (TNFR) superfamily members accounted for {\textgreater} 5{\%} of all microarray probes for genes with high expression in protective effector CD4 T cells, corresponding to a {\~{}}16-fold enrichment compared to the frequency of this class among all genes measured on the microarray (Fisher's Exact test P {\textless} 0.0001). Because TNF(R) superfamily molecules are potent mediators of inflammatory responses, we focused on the expression patterns of TNF(R) superfamily molecules across all six populations of T cells and identified genes for which the expression was significantly different for any comparison. KLRG1 − parenchy-mal effectors and KLRG1 + intravascular effectors showed different patterns of expression of these TNF(R) superfamily molecules (Fig. 1b,c), with the majority being expressed to a much greater extent in parenchymal effector CD4 T cells. Tnfsf5 (which encodes CD40L) 12 , Tnfsf14 (which encodes LIGHT) 13 , Lta (which encodes LT$\alpha$) 14 and Tnfrsf9 and Tnfsf9 (which encode 4-1BB and 4-1BB ligand, respectively) 15 were all},
author = {Sallin, Michelle A and Kauffman, Keith D and Riou, Catherine and {Du Bruyn}, Elsa and Foreman, Taylor W and Sakai, Shunsuke and Hoft, Stella G and Myers, Timothy G and Gardina, Paul J and Sher, Alan and Moore, Rashida and Wilder-Kofie, Temeri and Moore, Ian N and Sette, Alessandro and {Lindestam Arlehamn}, Cecilia S and Wilkinson, Robert J and Barber, Daniel L},
doi = {10.1038/s41564-018-0231-6},
file = {:C$\backslash$:/Users/Claire/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sallin et al. - 2018 - Host resistance to pulmonary Mycobacterium tuberculosis infection requires CD153 expression.pdf:pdf},
issn = {20585276},
journal = {Nature Microbiology},
keywords = {fund{\_}ack,letter},
mendeley-tags = {fund{\_}ack,letter},
number = {11},
pages = {1198--1205},
pmid = {30202016},
publisher = {Nature Publishing Group},
title = {{Host resistance to pulmonary \textit{Mycobacterium tuberculosis} infection requires CD153 expression}},
url = {https://doi.org/10.1038/s41564-018-0231-6},
volume = {3},
year = {2018}
}

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