The function of CTLA4 during the in vivo immune response to infectious disease.

摘要

CD4+ T cells play a key role in the adaptive immune response to foreign antigens. For T cells to be activated, two signals are required. The first signal is delivered through antigen recognition by the T cell receptor. A second, or costimulatory, signal is also required for optimal activation of T cells. CD-28 ligation by B7 is a potent mediator of positive costimulation. In contrast, B7 ligation of CTLA4 (CD 152), a homologue of CD28, provides a critical downregulatory signal. Recent data has suggested that CTLA4 may also share some stimulatory functions with CD28. Because costimulatory molecule interactions are critical for many immune responses, a greater understanding of CTLA4 function may promote development of immunotherapies where enhancement or inhibition of the immune response would be clinically beneficial. This research was directed at developing a greater understanding of CTLA4 function in the immune response to infectious disease. A murine model of gastrointestinal nematode infection, Heligmosomoides poligyrus, was utilized in this research to investigate the role of CTLA4 after onset of infection, once naïve T cells have differentiated to effector T cells. These data support a negative regulatory role for CTLA4 late in the response. Blockade of CTLA4 by in vivo administration of anti-CTLA4 antibody enhanced the polarized Th2 response to H. poligyrus, resulting in increased serum concentrations of immunoglobulins, IL-4 secretion, and T and B cell activation. Further evidence of enhanced immune response upon CTLA4 blockade was provided in another nematode model, Trichuris muris. Anti-CTLA4 antibody treatment increased serum immunoglobulin concentrations and T and B cell activation. The treatment also caused immune deviation from Th1 to Th2, as evidenced by decreased IFNγ and increased IL-4 secretion. These data are consistent with a model for Th1 versus Th2 cell differentiation which describes the decision as based on the balance between strength of signal and innate response. On a molecular level, the phosphorylation events following CTLA4 blockade were examined, and intracellular binding partners for CTLA4 and CD28 were identified. The dependence of effector T cells upon continued combined CTLA4/CD28 signaling was also explored.