The role of CD28-mediated costimulation in antigen-specific and allo-specific immune responses.

摘要

CD28 is an important costimulatory molecule that regulates T cell proliferation, survival, and effector function. Numerous studies indicate that blockade of CD28 engagement with its ligands, B7-1 and B7-2, not only profoundly affects the onset and progression of several autoimmune diseases but also inhibits the rejection of many kinds of transplanted organs and tissues. Although CD28/B7 costimulation appears to be a critical regulator of autoimmunity and graft rejection, the mechanisms involved in these immune processes are complex and can be influenced by a variety of factors. The studies presented in this dissertation were designed to selectively examine the role of CD28-mediated costimulation in antigen-specific and direct allo-specific immune responses using T cell receptor transgenic mouse models. First, employing transgenic T cell in vitro systems, increased CD28 ligation was shown to enhance CD4 + T proliferation and induce T helper cell differentiation toward a Th2 phenotype in an IL,4-dependent manner. Increased CD28 ligation also enhanced the production of MIP-1α, a T cell chemokine important for migration to sites of inflammation. Thus, the studies presented in this dissertation demonstrated that increasing the strength of CD28 ligation specifically influences the overall quality of immune responses, indicating that modulation of the strength of CD28 ligation in vivo may alter the onset or progression of autoimmune diseases regulated by certain Th cell phenotypes. Second, using a unique transgenic mouse model, the role of CD28 in the rejection of directly presented alloantigen was explored in vivo. The studies determined that CD4+ T cells restricted to direct antigen presentation are sufficient for the rejection of skin, but not heart or islet, allografts. Furthermore, the data support a B7-independent pathway for skin rejection in this model. A novel in vitro CFSE-labeling system showed that epidermal Langerhans cells are a distinctive APC subset that, contrary to APCs resident in the spleen, efficiently directly present alloantigen to CD4+ T cells in the absence of CD28/B7 costimulation. Thus, the results from these studies reveal new information regarding the pleiotropic effect of CD28 on T cell effector function and immune regulation.