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Tuberculosis Mycobacterium Immune Response to Diabetic Mice Display Diabetic Mice Display a Delayed Adaptive Immune Response to Mycobacterium tuberculosis This information is current as Therese Vallerskog, Gregory W. Martens and Hardy of September 26, 2021. Kornfeld J Immunol 2010; 184:6275-6282; Prepublished online 26 April 2010; doi: 10.4049/jimmunol.1000304 http://www.jimmunol.org/content/184/11/6275 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/04/23/jimmunol.100030 Material 4.DC1 http://www.jimmunol.org/ References This article cites 34 articles, 13 of which you can access for free at: http://www.jimmunol.org/content/184/11/6275.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Diabetic Mice Display a Delayed Adaptive Immune Response to Mycobacterium tuberculosis Therese Vallerskog, Gregory W. Martens, and Hardy Kornfeld Diabetes mellitus (DM) is a major risk factor for tuberculosis (TB) but the defect in protective immunity responsible for this has not been defined. We previously reported that streptozotocin-induced DM impaired TB defense in mice, resulting in higher pulmonary bacterial burden, more extensive inflammation, and higher expression of several proinflammatory cytokines known to play a pro- tective role in TB. In the current study, we tested the hypothesis that DM leads to delayed priming of adaptive immunity in the lung- draining lymph nodes (LNs) following low dose aerosol challenge with virulent Mycobacterium tuberculosis. We show that M. tuberculosis-specific IFN-g–producing T cells arise later in the LNs of diabetic mice than controls, with a proportionate delay in recruitment of these cells to the lung and stimulation of IFN-g–dependent responses. Dissemination of M. tuberculosis from lung to LNs was also delayed in diabetic mice, although they showed no defect in dendritic cell trafficking from lung to LNs after Downloaded from LPS stimulation. Lung leukocyte aggregates at the initial sites of M. tuberculosis infection developed later in diabetic than in nondiabetic mice, possibly related to reduced levels of leukocyte chemoattractant factors including CCL2 and CCL5 at early time points postinfection. We conclude that TB increased susceptibility in DM results from a delayed innate immune response to the presence of M. tuberculosis-infected alveolar macrophages. This in turn causes late delivery of Ag-bearing APC to the lung draining LNs and delayed priming of the adaptive immune response that is necessary to restrict M. tuberculosis replication. The Journal of Immunology, 2010, 184: 6275–6282. http://www.jimmunol.org/ pproximately one third of the world’s population is in- 439 million by 2030 (3). Of particular concern is the rapid increase fected with Mycobacterium tuberculosis, the causative in DM in developing countries with a high burden of TB (4). A agent of tuberculosis (TB), but this infection remains Despite the public health threat posed by these convergent epi- latent throughout life in ∼90% of infected individuals. For those demics, the immunological basis for TB susceptibility in DM is not ∼10% of M. tuberculosis-infected persons who develop active well understood. Wepreviouslypublished the first report oflow-dose disease, the inability to mount or to maintain an immune response aerosol M. tuberculosis infection in mice with streptozotocin that enforces latent TB infection results from diverse genetic and (STZ)-induced DM (5). Mice with chronic ($12 wk) but not acute acquired risk factors. Among the latter, HIV/AIDS has received (,4 wk) DM had a higher plateau bacterial burden and more lung by guest on September 26, 2021 much attention due to the dramatic increase in relative risk asso- inflammation by 8 wk postinfection (p.i.) compared with eugly- ciated with CD4+ T cell deficiency and the observation that TB is cemic controls. The finding that acute STZ-induced hyperglycemia the leading cause of death in that population (1). It has been rec- and hypoinsulinemia have no major impact on TB defense sug- ognized for some time that diabetes mellitus (DM) increases the gested that impaired host defense in DM could, like many other risk for TB, but the magnitude of this effect has only recently been diabetic complications, result from biochemical effects of pro- appreciated. In a review of 13 observational studies addressing the longed hyperglycemia. Despite evidence of increased susceptibil- association of DM and TB disease, Jeon and Murray (2) determined ity, mice with chronic DM and infected with M. tuberculosis for .4 that the global population-attributable risk is comparable to that of wk exhibited no evident deficiency in leukocyte recruitment to the HIV/AIDS. Although the immune dysfunction associated with DM lungs or in the expression of key cytokines relevant to TB defense. is not as severe as that caused by HIV infection, DM is a more On the contrary, diabetic mice had significantly more pulmonary common disorder than HIV/AIDS. The worldwide prevalence of T cells, macrophages, and neutrophils than controls, whereas the DM in 2010 is estimated to be 285 million and is predicted to reach relative proportions of these different populations were comparable to the controls. Similarly, the diabetic mice had more IFN-g, IL-1b, and TNF-a protein in their lungs than control mice at 8 wk or longer Department of Medicine, University of Massachusetts Medical School, Worcester, after M. tuberculosis infection. Mice with chronic DM were ca- MA 01655 pable of arresting M. tuberculosis replication in the lung, but at .1 Received for publication January 28, 2010. Accepted for publication March 22, 2010. log higher plateau bacterial burden than controls. Although diabetic This work was supported in part by National Institutes of Health Grant HL081149 (to mice had expressed more IFN-g than controls at later time points, H.K.). Core resources supported by the Diabetes Endocrinology Research Center they had significantly lower IFN-g expression 2 wk p.i., suggesting Grant DK32520 were also used. that TB susceptibility might result at least in part from a delay in Address correspondence and reprint requests to Dr. Hardy Kornfeld, Department of initiating M. tuberculosis-specific adaptive immunity. Medicine, LRB-303, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. E-mail address: [email protected] In the current study, we sought to gain further insight to the basis The online version of this article contains supplemental material. of TB susceptibility in mice with chronic STZ-induced DM (STZc). Abbreviations used in this paper: Ctrl, control; DC, dendritic cell; DM, diabetes We used STZ for these experiments to produce uniform hypergly- mellitus; HbA1c, hemoglobin A1c; i.t., intratracheal; LN, lymph node; na, not avail- cemia without the potentially confounding effects of autoimmunity able; p.i., postinfection; PPD, purified protein derivative; STZ, streptozotocin; STZc, in NOD mice that might interfere with the interpretation of any mice with chronic STZ-induced DM; TB, tuberculosis. observed TB susceptibility and in view of the fact that hypergly- Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 cemia drives most diabetic complications. We report in this study www.jimmunol.org/cgi/doi/10.4049/jimmunol.1000304 6276 DELAYED TUBERCULOSIS IMMUNITY IN DIABETIC MICE that the earliest appearance of M. tuberculosis-specific IFN-g– the expression of CD3, CD4, CD8, F4/80, Gr-1, and CD19. No differences producing T cells in the thoracic lymph nodes (LNs) and subse- were observed between control and STZc mice in the total number of these quently in the lung occurred later in STZc mice than control mice. different leukocyte types prior to M. tuberculosis challenge or at days 7, 14, 21, and 28 p.i. (Supplemental Fig. 2A). This is consistent with our prior Delivery of M. tuberculosis bacilli to the pulmonary LNs was also observations (5). Leukocytes from lung-draining LNs were evaluated for delayed in STZc mice but we found no evidence for impaired the expression of CD11c, CD19, CD4, and CD8 at days 12, 15, 18, and 21 dendritic cell (DC) trafficking from the lung to the LNs in STZc p.i., with no proportionate differences observed between control and STZc mice challenged with intratracheal (i.t.) LPS, nor any difference in mice (Supplemental Fig. 2B). the expression of MHC class II or costimulatory molecules on mi- Ex vivo T cell restimulation grating DCs. Examination of lung histopathology from early time IFN-g secreted from lung leukocytes and thoracic LN lymphocytes was points after M. tuberculosis infection demonstrated a delay in re- detected using an IFN-g Ab ELISPOT pair (BD Biosciences, San Jose, CA), cruitment of myeloid cells to sites of initial macrophage infection in MultiScreen-IP ELISPOT plates (Millipore, Billerica, MA), streptavidin- the lungs of STZc mice. In a similar time frame, these mice also had alkaline phosphatase (Mabtech, Nacka Strand, Sweden), 5-bromo-4-chloro- reduced expression of CCL2 and CCL5, chemokines that stimulate 3-indolyl phosphate/nitro blue tetrazolium, BCIP/NBT (Sigma-Aldrich), and M. tuberculosis Ag85 peptide (Ag85A243–260 sequence Ac-QDAYN- migration of macrophages and DCs. These findings pinpoint a criti- AGGGHNGVFDFPSDG-amide; Twentyfirst Century Biochemicals, Marl- cal lesion in protective immunity resulting from chronic hypergly- boro, MA) for stimulation of T cells.
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