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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.