Lymphocyte Growth Regulation

In the area of immune cell activation, our lab has mostly focused on T cells. These cells originate in the bone marrow and mature in the thymus, where only a small number survive the process of maturation. Thymic education is responsible for self-recognition and central tolerance. T cells share structural features of the T cell antigen receptor. A peculiarity of the T cell receptor is that it requires foreign antigens to be presented in the context of self; that is, the cells only see antigen when it is complexed with a molecule from the major histocompatibility complex (MHC). For many years, we have wondered what keeps normal T lymphocytes from being activated all the time. After all, we are constantly bombarded with antigens. Initially, we focused on signals that activate the cell cycle machinery. The conventional wisdom then, and until a few years ago was that, because T cells are highly specific (they only recognize one antigen among the millions possible), they would remain quiescent until they saw their precise antigen and would be driven through the cell cycle by pathways that regulate the cell cycle machinery. Specifically, activation of CDK4 was a central mediator of the transition from the G0 to the G1 phase. But the dilemma was that no other cell in the body seemed to behave this way. In fact, our work showed that the machinery that controls proliferation in lymphocytes was similar to that present in other cells (remarkably, this is similar to the machinery that controls cell division in all eukaryotic organisms, including yeast!) In the latter 1990’s and the early 2000’s, several groups proposed that, in fact, T lymphocytes were not unlike other cells, and that they were quite ready to be activated at any time. However, this activation was kept in check both by specific proteins that were called “negative regulators” and by a series fo cells in teh immune system called "regulatory cells" (including regulatory T cells or Tregs, myeloid derived suppressor cells or MDSCs, and possibly regulatory dendritic cells). We pursued the concept of intrinsic negative regulation and showed that proteins such as NFATc2, Tob-1, and TGF-beta are important intrinsic negative regulators of T cell activation. Indeed, recent work shows that one of the ways that smoking can affect the immune system, and probably contribute to many of the diseases associated with tobacco use, is by nicotine “enforcing” negative regulation - that is, it prevents T lymphocytes from responding to foreign invaders - through the action of this NFATc2 protein. Our lab continues to explore mechanisms that control lymphocyte activation, as well as how nicotine or tobacco products affect the immune system with a renewed focus on the role of cholinergic receptors, MHC antigens, and other molecules in negative regulation.

Selected Results from Our Laboratory

Below is a list of selected publications from our laboratory on cancer immunology and immunotherapy. For more extensive details please see our list of publications. You can also contact our laboratory staff if you have questions or requests for more specific information.

Review and Opinion Articles
Modiano JF, Johnson LDS, Bellgrau D. (2008). Negative regulators in homeostasis of naïve peripheral T cells. Immunol Res, 41(2), 137-153.

Chitko-McKown CG and Modiano JF. (1997). Clues to immune function and oncogenesis provided by events that activate the cell cycle machinery in normal human T cells. J Leukocyte Biol 62, 430-437.

Research Articles
Willoughby Sr JA, Sundar SN, Cheung M, Tin AS, Modiano J, Firestone GL. (2009). Artemisinin blocks prostate cancer growth and cell cycle progression by disrupting Sp1 interactions with the cyclin-dependent kinase-4 promoter and inhibiting CDK4 gene expression. J Biol Chem, 284(4), 2203-2213 (Epub. 2008 Nov 17 PMID: 19017637)

Results demonstrate that a key event in the artemisinin anti-proliferative effects in prostate cancer cells is transcriptional down-regulation of CDK4 expression by disruption of Sp1 interactions with the CDK4 promoter.

Jubala CM, Lamerato AR, Borakove M, Lang J, Gardner L, Coffey D, Helm KM, Schaack J, Baier M, Cutter GR, Bellgrau D, Modiano JF. (2009) MHC-dependent desensitization of intrinsic anti-self reactivity. Cancer Immunol Immunother, 58(2), 171-185. (Epub 2008 Jun 4 DOI 10.1007/s00262-008-0535-0)

Evidence for links between MHC-dependent signals and mechanisms that prevent spontaneous or inappropriate activation of self-reactive T cells.

Frazer-Abel AA, Baksh S, Fosmire SP, Willis D, Pierce AM, Meylemans H, Linthicum DS, Coons T, Burakoff SJ, Bellgrau D, Modiano JF. (2004). Nicotine activates NFATc2 and prevents cell cycle entry in T cells. J Pharmacol Exp Ther, 311, 758-769.

Identification of NFAT activation in lymphocytes and endothelial cells by nicotine and description of how nicotine co-opts a major mechanism that enforces T cell negative regulation.

Baksh S, Widlund HR, Frazer-Abel AA, Du J, Fosmire S, Fisher DE, DeCaprio JA, Modiano JF, Burakoff SJ. (2002). NFATc2-mediated repression of cyclin-dependent kinase 4 expression. Mol Cell, 10, 1071-1081.

Characterization of a major mechanism that controls quiescence and enforces tolerance in T cells.

Modiano JF, Mayor J, Ball C, Fuentes MK, Linthicum DS. (2000). Cdk4 expression and activity are required for cytokine responsiveness in T cells. J Immunol, 165, 6693-6702.

Identification of CDK4 as the major G0/G1 transition kinase in T cells, controlling not only proliferation, but also aspects of tolerance

Modiano JF, Mayor J, Ball C, Chitko-McKown CG, Sakata N, Domenico J, Lucas JJ, Gelfand EW. (1999). Quantitative and qualitative signaling differences determine T cell cycle entry and progression. Cell Immunol, 197, 19-29.

Characterization of the signals that define transition from G0 to G1 in T cells. An important contribution to understand signals that mediate T cell activation and pathways that participate in pathogenesis of lymphoma/leukemia

Modiano JF, Domenico J, Szepesi A, Terada N, Lucas JJ, and Gelfand EW (1995). Symmetry of the activation of cyclin-dependent kinases in mitogen and growth factor-stimulated T lymphocytes. Ann New York Acad Sci 766, 134-148.

Modiano JF, Domenico J, Szepesi A, Lucas JJ, Gelfand EW. (1994). Differential requirements for interleukin-2 distinguish the expression and activity of the cyclin-dependent kinases cdk4 and cdk2 in human T cells. J Biol Chem 269, 32972-32978.