Research Summary

Inflammation is an immediate response to infection or tissue injury. It is normally a beneficial response that results in recruitment of immune cells to the inflammatory site to fight infection. These cells also aid in tissue repair and the resolution of inflammatory response. The persistence of inflammation leads to chronic inflammatory diseases such as arthritis, inflammatory bowel diseases and atherosclerosis. These are an increasing problem in the Western world and cost our health system billions in long term care.

Our lab is interested in understanding the factors that regulate both the initiation and resolution of inflammation. CD44 is a cell adhesion molecule implicated in both phases and by learning how CD44 regulates these processes, we may discover new ways to resolve chronic inflammation.

Our immune system is our body’s natural defence against disease. Most of the time its potent action can combat 99% of the diseases we encounter, but should it misfire, it can also cause disease. Our immune system has two components, an immediate, innate response followed by a specific, adaptive response. A key cell type responsible for directing the appropriate immune responses is the dendritic cell. This cell is also crucial for preventing our immune system from attacking our own cells.

Our lab is interested in understanding the factors that control dendritic cell functions. CD45 is an immune cell specific, tyrosine phosphatase that can regulate the dendritic cell’s response to danger signals. We want to understand how it does this and how it affects the outcome of both the innate and adaptive immune responses. Factors that can modulate the immune response will be invaluable in helping us develop new regimes to prevent or cure disease.

Projects
  • Regulation of the immune response by the cell surface molecules, CD44 and CD45
  • How CD44 and CD45 expression by dendritic cells regulates the outcome of the innate and adaptive immune response
  • Publications

     
    Comprehensive List
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    Selected Publications

    1. WEISSER SB, KOZICKY LK, BRUGGER HK, NGOH EN, CHEUNG B, JEN R, MENZIES SC, SAMARAKOON A, MURRAY PJ, LIM CJ, JOHNSON P, BOUCHER JL, VAN ROOIJEN N, SLY LM. (2014) Arginase activity in alternatively activated macrophages protects PI3Kp110δ deficient mice from dextran sodium sulfate induced intestinal inflammation. Eur J Immunol. doi: 10.1002/eji.201343981. [Epub ahead of print]
    2. SAUNDERS AE, SHIM YA, JOHNSON P. (2014) Innate Immune Cell CD45 Regulates Lymphopenia-Induced T Cell Proliferation. J. Immunol. 193(6):2831-42.
    3. DIMITRIU PA, BOYCE G, SAMARAKOON A, HARTMANN M, JOHNSON P, MOHN WW. (2013) Temporal stability of the mouse gut microbiota in relation to innate and adaptive immunity. Environ. Microbiol. (2):200-10.
    4. BERNHARD W, BARRETO K, SAUNDERS A, DAHABIEH MS, JOHNSON P, SADOWSKI I. (2011) The Suv39H1 methyltransferase inhibitor chaetocin causes induction of integrated HIV-1 without producing a T cell response. FEBS Lett. 585(22):3549-54.
    5. RUFFELL, B., POON, G.F.T., LEE, S.M., BROWN, K.L., TJEW, S-L., COOPER. J., & JOHNSON, P. (2011) Differential use of chondroitin sulfate to regulate hyaluronan binding by CD44 in inflammatory and interleukin 4 (IL-4) activated macrophages. J. Biol. Chem. 286(22):19179-90.
    6. *BROWN, K.L., *POON, GFT., BIRKENHEAD, D., PENA, OM., FALSAFI, R., DAHGREN, C., KARLSSON, A., BYLUND, J., HANCOCK, R.E.W., & JOHNSON, P. (2011) Host Defense Peptide LL-37 Selectively Reduces ProInflammatory Macrophage Responses. J. Immunol. 186(9):5497-505.
    7. MAESHIMA, N., POON, G.F.T., DOSANJH, M., FELBERG, J., LEE, S.S.M., CROSS, J., BIRKENHEAD, D., JOHNSON, P. (2011) Hyaluronan binding identifies the most rapidly proliferative activated and memory T cells. Eur. J. Immunol. 41(4):1108-19.
    8. WONG, NKY., LAI, JCY., MAESHIMA, N. & JOHNSON, P. (2011) CD44-mediated elongated T cell spreading requires Pyk2 activation by Src family kinases, extracellular calcium, phospholipase C and phosphatidylinositol-3 kinase. Cell Signalling 5:812-9.
    9. LAI, J.C.Y., WLODARSKA, M., LUI, D. Abraham, N. & Johnson, P. (2010) CD45 regulates migration, proliferation and progression of early thymocyte progenitors. J. Immunol 185:2059-70
    10. *LEFEBVRE, D., *LAI, J. C. Y., MAESHIMA, N., FORD, Jl., BIRKENHEAD, D., WONG, ASL., CROSS, Jl., & JOHNSON, P. (2010) CD44 interacts directly with Lck in a zinc dependent manner. Mol. Immunol. 47:1882-1889.
    11. SAUNDERS, A.E. & JOHNSON, P. (2010) Modulation of immune cell signalling by the leukocyte common tyrosine phosphatase, CD45 Cell. Signal 22:339-48.
    12. CROSS, J.L. & JOHNSON, P. (2009) Tyrosine phosphorylation in immune cells: direct and indirect effects on Toll-like receptor induced proinflammatory cytokine production. Crit. Rev. Immunol. 29:347-67.
    13. JOHNSON, P. & RUFFELL, B. (2009) CD44 and its role in inflammation and inflammatory disease. Inflamm. Allergy Drug Targets. 8:208-20.
    14. RUFFELL, B., & JOHNSON, P. (2009) The regulation and function of hyaluronan binding by CD44 in the immune system. In HyaluronanToday www.glycoforum.gr.jp/science/hyaluronan/HA32/HA32E.html
    15. CROSS, JL., KOTT, K., MILETIC, T. & JOHNSON, P. (2008) CD45 regulates TLR-induced proinflammatory cytokine and IFN-beta secretion in dendritic cells. J. Immunol. 180(12): 8020-8029.
    16. *WONG, NKY, *LAI, JCY, MAESHIMA, N., BIRKENHEAD, D., SHAW, A, & JOHNSON, P. (2008) CD45 down-regulates CD44-mediated Lck activation and modulates actin rearrangement in T cells. J. Immunol. 181:7033-7043.
    17. RUFFELL, B. & JOHNSON, P. (2008) Hyaluronan induces cell death in activated T cells through CD44. J.Immunol. 181:7044-7054.
    18. MAKSUMOVA, L., WANG, Y., WONG, N.K., LE, H.T., PALLEN, C.J. & JOHNSON, P. (2007) Differential function of PTPalpha and PTPalpha Y789F in T cells and regulation of PTPalpha phosphorylation at Tyr-789 by CD45. J. Biol. Chem. 282(29): 20925-20932.
    19. STILLMAN, B.N., HSU, D.K., PANG, M., BREWER, C.F., JOHNSON, P. LIU, F.T. & BAUM, L.G. (2006) Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death. J. Immunol. 176: 778 -789.
    20. BONDER, C.S., CLARK, S.R., NORMAN, M.U., JOHNSON, P. & KUBES, P. (2006) Use of CD44 by CD4+ Th1 and Th2 lymphocytes to roll and adhere Blood, 107: 4798-4806.
    21. CHOW, M., DHANJI, S., CROSS. J., JOHNSON, P. & TEH, H.S. (2006) H2-M3-restricted T
      cells participate in the priming of antigen-specific CD4+ T cells. J. Immunol. 177: 5098-5104.
    22. RUFFELL, B. & JOHNSON, P. (2005) Chondroitin sulfate addition to CD44H negatively regulates hyaluronan binding. Biochem. Biophys. Res. Comun. 334(2). 306-312.
    23. TJEW, S.L., BROWN, K.L., KANNAGI, R. & JOHNSON, P. (2005) Expression of N-acetylglucosamine 6-O-sulfotransferases (GlcNAcGSTs)-1 and -4 in human monocytes: GlcNAc6ST-1 is implicated in the generation of the 6-sulfo N-acetyllactosamine/Lewis x epitope on CD44 and is induced by TNF-alpha. Glycobiology 15(7). 7C-13C.
    24. WANG, Y., & JOHNSON, P. (2005) Expression of CD45 lacking the catalytic protein tyrosine phosphatase domain modulates Lck phosphorylation and T cell activation. J. Biol. Chem. 280(14). 14318-14324.
    25. BROWN, K.L., BIRKENHEAD, D., LAI, J.C., Li, L., Li, R. & JOHNSON, P. (2005) Regulation of hyaluronan binding by F-actin and colocalization of CD44 and phosphorylated ezrin/radixin/moesin (ERM) proteins in myeloid cells. Exp. Cell Res. 303(2). 400-414.
    26. KHAN, A.I., KERFOOT, S.M., Heit, B., LIU, L., ANDONEGUI, G., RUFFELL, B., JOHNSON, P. & KUBES, P. (2004) Role of CD44 and hyaluronan in neutrophil recruitment. J. Immunol. 173(12). 7594-7601.
    27. FELBERG, J., LEFEBVRE, D.C., LAM, M., WANG, Y., NG, D.H., BIRKENHEAD, D., CROSS, J.L. & JOHNSON, P. (2004) Subdomain X of the kinase domain of Lck binds CD45 and facilitates dephosphorylation. J. Biol. Chem. 279(5). 3455-3462.
    28. LEFEVBRE, D. C., FELBERG, J., CROSS, J. L., & JOHNSON, P. (2003) The non-catalytic domains of Lck regulate its dephosphorylation by CD45. Biochim. Biophys. Acta 1650:40-49.
    29. FORTIN, M., STEFF, A-M., FELBERG, J., DING, I., SCHRAVEN, B., JOHNSON, P. & HUGO, P. (2002) Apoptosis mediated through CD45 is independent of its phosphatase activity and association with LPAP. J. Immunol. 168:6084-6089.
    30. DELCOMMENNE, M., KANNAGI, R. & JOHNSON, P. (2002) TNF-a alters the carbohydrate sulfation of CD44: induction of 6 sulfo N-acetyl glucosamine on N and O-linked glycans. Glycobiology 12:613-622.
    31. LI, R., WONG, N., JABALI, M. D. & JOHNSON, P. (2001) CD44 initiated cell spreading is mediated by src family kinases and pyk2 and is negatively regulated by CD45. J. Biol. Chem 276:28767-28773.
    32. IRIE-SASAKI, J., SASAKI, T., MATSUMOTO, W., OPAVSKY, A., CHENG, M., WELSTEAD, G., GRIFFITHS, E., KRAWCZYK, C., RICHARDSON, C. D., AITKEN, K., ISCOVE, N., KORETZKY, G., JOHNSON, P., LIU, P., ROTHSTEIN, D. M. & PENNINGER, J. M. (2001) CD45 is a JAK phosphatase and negatively regulates cytokine receptor signaling. Nature 409:349-54.
    33. BROWN, K., MAITI, A. & JOHNSON, P. (2001) Role of sulfation in CD44 mediated hyaluronan binding induced by inflammatory mediators in human CD14+ peripheral blood monocytes. J. Immunol. 167:5367-5374.
    34. JOHNSON, P., MAITI, A., BROWN, K. & LI, R. (2000) A role for the cell adhesion molecule, CD44, and sulfation in leukocyte-endothelial cell adhesion during an inflammatory response. Biochem. Pharm. 59:455-65.
    35. NG, D. H. W., FELBERG, J. & JOHNSON, P. (2000) Determination of CD45 tyrosine phosphatase activity in T lymphocytes. In: Methods in Molecular Biology : Protocols in T cell development and activation. (ed: Kearse, K. P.) Humana Press Chapter 24, p289-300.
    36. FELBERG, J. & JOHNSON, P. (2000) Stable interdomain interaction within the cytoplasmic domain of CD45 increases enzyme stability. Biophys. Biochem. Res. Comm. 271:292-298.
    37. JOHNSON, P. & FELBERG, J. (2000) CD45: A key regulator of lck and T cell activation. Mol. Asp. Immunobiol. 1:156-159.
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