Asthma and other allergic diseases are driven by excessive helper T cell responses to antigen. Thus, helper T cells are attractive targets for new therapeutics. One long-term objective of my lab is to define intracellular signaling pathways that regulate expression of the allergy-promoting cytokines IL-4, -5 and -13 by helper T cells. In previous work, we showed that the peptidyl-prolyl isomerase cyclophilin A (CypA) is a regulator of helper T cell responses. CypA is an enzyme that catalyzes isomerization of peptide bonds adjacent to proline residues. Such catalytic events are known to act as “switches” that regulate protein function via conformational changes. Mice lacking CypA develop inflammation containing eosinophils and mast cells, which both have key roles in allergic responses. Helper T cells lacking CypA overproduce IL-4, -5 and -13 and show increased activation of the key signaling molecule phospholipase C-gamma1 (γ1). These results indicate that CypA functions to repress signal transduction events in helper T cells. Current work is focused on defining the molecular targets of CypA. To achieve this, we are employing molecular biology, biochemistry and mouse models for athma and other human diseases.
A second topic of study is a novel mutant mouse called Justy. Justy mice lack mature B cells, owing to a block at an early stage of B cell development. The mutation in Justy mice affects a novel transcription factor that likely functions as a modifier of chromatin structure. Current work is focused on determining the function of this protein during B cell development and identifying its downstream target genes.
Early B Cell Progenitors Deficient for GON4L Fail To Differentiate Due to a Block in Mitotic Cell Division.
Barr JY, Goodfellow RX, Colgan DF, Colgan JD.
J Immunol. 2017 May 15;198(10):3978-3988. doi: 10.4049/jimmunol.1602054. Epub 2017 Apr 5.
Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation.
Phong BL, Avery L, Sumpter TL, Gorman JV, Watkins SC, Colgan JD, Kane LP.
J Exp Med. 2015 Dec 14;212(13):2289-304. doi: 10.1084/jem.20150388. Epub 2015 Nov 23.
Identification of hematopoietic-specific regulatory elements from the CD45 gene and use for lentiviral tracking of transplanted cells.
Duong KL, Das S, Yu S, Barr JY, Jena S, Kim E, Zavazava N, Colgan JD, Xue HH, Levasseur DN.
Exp Hematol. 2014 Sep;42(9):761-72.e1-10. doi: 10.1016/j.exphem.2014.05.005. Epub 2014 May 20.
Regulation of T cell responses by the receptor molecule Tim-3.
Gorman JV, Colgan JD.
Immunol Res. 2014 Aug;59(1-3):56-65. doi: 10.1007/s12026-014-8524-1. Review.
Tim-3 directly enhances CD8 T cell responses to acute Listeria monocytogenes infection.
Gorman JV, Starbeck-Miller G, Pham NL, Traver GL, Rothman PB, Harty JT, Colgan JD.
J Immunol. 2014 Apr 1;192(7):3133-42. doi: 10.4049/jimmunol.1302290. Epub 2014 Feb 24.