Intestinal Host Defense: Toggling between immune tolerance and immune protection
The intestinal mucosa is the largest lymphoid organ, as assessed by the quantity of antibody produced, the number of resident leukocytes, and its surface area exposure to the environment (greater than that of a tennis court). Confounding the situation, the wall of the gut is continuously bathed by bacteria, parasites, fungi, amoebae, viruses, mitogens, toxins, and immunogenic food proteins. Therefore, a complex multi-tiered host defense system has evolved in the gut that can be divided into four interactive functions:
- Barrier exclusion by an actively regenerating epithelial cell monolayer.
- Innate inflammatory responses mediated by local synthesis of pro- and anti-inflammatory cytokines and antimicrobial peptides.
- Acquired immune responses regulated by T lymphocytes.
- Host-microbiome colonization and differentiation.
Our laboratory focuses on the mechanisms that regulate these systems:
- Effects on intestinal permeability associated with HIV infection or inflammatory bowel disease (IBD), due to changes in the the structure, composition, and function of the tight junctional complex that regulates paracellular epithelial continuity.
- In murine models of acute and chronic intestinal inflammation, we investigate the temporal expression and regulation of pro-inflammatory and anti-inflammatory cytokines in response to gut injury induced by ischemia associated with illicit drug abuse (opioids, methamphetamine, cocaine), and in a transgenic mouse that models human inflammatory bowel disease.
- Dysbiosis in the HIV+, drug abuse, or IBD gut, and its consequent effect on host mucosal immune protection.
- Using transgenic murine models, we explore the mechanisms by which co-stimulatory and accessory molecules direct the development of immune tolerance as T cells migrate from the Peyer's patch to the gut wall.
- We characterize the biochemical, spatial, temporal, and structural organization of the signal transduction pathway initiating with the anti-specific T cell receptor, and differentially regulated in naïve, helper, effector, and mucosal T cells.
- We research the regulation of integrin affinity/avidity, expression, and activation in both naïve and memory T cells by the interstitial extracellular matrix, and how matrix-induced T cell polarization modulates the partitioning of the TCR/CD3 signaling complex in the plasma membrane.
Chung C.Y., Alden S.L., Fu P., Funderburg N.T., Levine A.D. "Progressive Proximal-to-Distal Reduction in Expression of the Tight Junction Complex in Colonic Epithelium of Virally-suppressed HIV+ Individuals." PLoS Pathog (2014) 10:e1004198; doi: 10.1371/journal.ppat.1004198. PMCID: PMC4072797.
Gill, T., Levine, A.D. "Mitochondrial derived hydrogen peroxide selectively enhances T cell receptor-initiated signal transduction." J. Biol Chem (2013) 288, 26246-26255; doi: 10.1074/jbc.M113.476895. Published online July 23, 2013. PMCID: PMC3764828
Meisch, J.P., Vogel, R.M., Schlatzer, D.M., Li, X., Chance, M.R., Levine, A.D. "Human β-defensin 3 induces STAT1 phosphorylation, tyrosine phosphatase activity, and cytokine synthesis in T cells." J Leukoc Biol (2013) 94, 459-471; doi:10.1189/jlb.0612300. Published online June 26, 2013. PMCID: PMC3747125.
Funderburg, N.T., Stubblefield Park, S.R., Sung, H.C., Hardy, G., Clagett, B., Ignatz-Hoover, J., Harding, C.V., Fu, P., Katz, J.A., Lederman, M.M., Levine, A.D. "Circulating CD4+ and CD8+ T cells are activated in IBD and are associated with plasma markers of inflammation." Immunology (2013) 140, 87–97; doi: 10.1111/imm.12114. Published online 22 April 2013. PMCID: PMC3809709.
Meisch, J.P., Nishimura, M., Vogel, R.M., Sung, H.C., Bednarchik, B.A., Ghosh, S.K., Fu, P., McCormick, T., Weinberg, A., Levine, A.D."Human β-defensin 3 peptide is increased and redistributed in Crohn's ileitis." Inflamm Bowel Dis (2013) 19, 942-953. doi: 10.1097/MIB.0b013e318280b11a. Published online 18 March 2013. PMID: 23511030. NIHMSID 457550. PMCID: PMC3746836.
Das, L.M., Torres-Castillo, M.D.L.A., Gill, T., Levine A.D. "TGF-β conditions intestinal T cells to express increased levels of miR-155, associated with down-regulation of IL-2 and itk mRNA." Mucosal Immunology. (2013) 6, 167–176. doi: 10.1038/mi.2012.60. Epub July 11, 2012; PMCID: PMC3504619
Goodman WA, Young AB, McCormick TS, Cooper KD, Levine A.D. "Stat3 Phosphorylation Mediates Resistance of Primary Human T Cells to Regulatory T Cell Suppression." J. Immunol. 186:3336-3345 (2011); published ahead of print February 9, 2011, doi:10.4049/jimmunol.1001455; PMID: 21307288; PMC3133678.
Franko, J.L., Levine, A.D. "Antigen-independent adhesion and cell spreading by Inducible Co-stimulator engagement inhibits T cell migration in a PI-3 K dependent manner." J. Leuko. Biol. 85(3): 526-538 (2009); PMCID: PMC2653947.
Das, L., Levine, A.D. "TGF- β inhibits IL-2 Production and Promotes Cell Cycle Arrest in T Cell Receptor-Activated Effector/Memory T Cells in the presence of Sustained TCR Signal Transduction." J. Immunol. 180(3): 1490-1498 (2008).
Etling, M.R., Davies, S., Campbell, M., Redline, R.W., Pingfu Fu, P., Levine, A.D. "Maturation of the mucosal immune system underlies colitis susceptibility in interleukin-10 deficient (IL-10-/-) mice." J. Leuko. Biol. 82:311-319 (2007)
Rivera Reyes, B.M., Danese, S., Sans, M., Fiocchi, C., Levine, A.D. "Redox equilibrium in mucosal T cells tunes the intestinal TCR signaling threshold." J. Immunology 175: 2158-2166 (2005).
Schade, A.E, Levine, A.D. "Cutting Edge: Extracellular Regulated Kinases 1/2 (ERK-1/2) function as integrators of T cell receptor signal strength." J Immunol. 172: 5828-5832 (2004).
Sturm, A., Krivacic, K.A., Fiocchi, C., Levine, A.D. "Dual Function of the Extracellular Matrix: Stimulatory for Cell Cycle Progression of Naive T cells and Anti-Apoptotic for Memory T Cells." J. Immunol. 173: 3889-3900 (2004).
Krivacic, K.A., Levine, A.D. "Extracellular matrix conditions T cells for adhesion to tissue interstitium." J. Immunol. 170: 5034-5044 (2003).
Schade, A.E., Levine, A.D. "Phosphatases in concert with kinases set the gain for signal transduction through the T cell receptor." Molecular Immunology 40 (8): 531-537 (2003).
Spencer, D.M., Veldman, G.M., Banerjee S., Willis, J., Levine, A.D. "Distinct inflammatory mechanisms mediate early versus late colitis in IL-10-deficient mice." Gastroenterology 122:94-105 (2002).
Schade, A.E., Levine, A.D. "Lipid raft heterogeneity in human peripheral blood T lymphoblasts as a mechanism for regulating the initiation of TCR signal transduction." J. Immunology 168:2233-2239 (2002).
Jump, R.J., Levine, A.D. "Murine Peyer's Patches Favor Development of an IL-10-Secreting, Regulatory T Cell Population." J. Immunology 168 (12): 6113-6119 (2002).
Pandiyan, P., Younes, S. A., Ribeiro, S. P., Talla, A., McDonald, D., Bhaskaran, N., Levine, A. D., Weinberg, A., and Sekaly, R. P. “Mucosal Regulatory T Cells and T Helper 17 Cells in HIV-Associated Immune Activation.” Front Immunol (2016) 7, 228; doi: 10.3389/fimmu.2016.00228.
Pagano, M.E., Maietti, C.M., Levine, A.D. “Risk factors of repeated infectious disease incidence among substance-dependent girls and boys court-referred to treatment.” Am J Drug Alcohol Abuse (2015) 41(3). 230-236; Early Online: 1–7. DOI: 10.3109/00952990.2014.939753.
Klatt, N.R., Harris, L.D., Vinton, C.L., Sung, H., Briant, J.A., Tabb, B., Morcock, D., McGinty, J.W., Lifson, J.D., Lafont, B.A., Martin, M.A., Levine, A.D., Estes, J.D., Brenchley, J.M. (2010). Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation and IL-17 production in the absence of SIV infection. Mucosal Immunology 3(4): 387–398.