The immune responses that cause transplant rejection and many autoimmune disorders such as diabetes mellitus are T cell-dependent. T cells responding to alloantigens or autoantigens produce cytokines and proliferate, leading to the differentiation of immune effector cells including T cells themselves, macrophages, and B cells. While a tremendous degree of proliferation occurs during this process, it is clear that a great deal of cell death occurs as well. The balance between survival and death is an important factor in determining the strength and longevity of the response. In the case of organ transplants, this initial response is manifest as acute rejection. An equally important immunologic event is the emergence of memory T cells, the small population of previously activated cells which do not die early in the response. In the case of organ transplantation, these memory cells mediate chronic rejection (the most common cause of late allograft loss, and a major clinical dilemma), and are important in providing help to B cells that produce alloantibody (the sine qua non of """"""""sensitized"""""""" patients, and a major contributor to extended times on transplant waiting lists). Recently, using dye-labeling techniques to both monitor and physically sort individual T cells as a function of proliferative status, we and others have shown that T cells responding to antigen exhibit surprising heterogeneity with respect to proliferation, and that this strongly correlates with cytokine production. We have also used mice transgenic for the cell survival gene bcl-xL to develop a model in which the effector function and the survival of a responding T cell can be uncoupled, allowing us to independently assess the contribution of these two immune parameters to the induction of memory or tolerance. These data suggest that cell survival is sufficient for the development of memory, even when effector function of T cells has been significantly compromised. In this application, we propose to use T cell receptor transgenic mice specific for alloantigen and nominal antigen to study immune responses during transplantation and immunization at the single-cell level.
In aim number l, we will determine if cell division plays an independent role in determining the functional outcome (tolerance vs. memory) of a T cell response.
In aim number 2, we will determine if cell death plays an active role in determining the functional outcome (tolerance vs. memory) of a T cell response. Together, these studies should greatly enhance our understanding as to how these phenomena interact to shape immune responses, facilitating the design of novel strategies to induce tolerance in transplantation and autoimmunity.
| Rowell, Emily A; Walsh, Matthew C; Wells, Andrew D (2005) Opposing roles for the cyclin-dependent kinase inhibitor p27kip1 in the control of CD4+ T cell proliferation and effector function. J Immunol 174:3359-68 |
| Wells, Andrew D; Liu, Qing-Hua; Hondowicz, Brian et al. (2003) Regulation of T cell activation and tolerance by phospholipase C gamma-1-dependent integrin avidity modulation. J Immunol 170:4127-33 |
| Kreisel, Daniel; Sankaran, David; Wells, Andrew D et al. (2002) Interleukin-2-mediated survival and proliferative signals are uncoupled in T lymphocytes that fail to divide after activation. Am J Transplant 2:120-8 |
| Wells, A D; Walsh, M C; Bluestone, J A et al. (2001) Signaling through CD28 and CTLA-4 controls two distinct forms of T cell anergy. J Clin Invest 108:895-903 |
