Multiple Layers of CD80/86-Dependent Costimulatory Activity Regulate Primary, Memory, and Secondary Lymphocytic Choriomeningitis Virus-Specific T Cell Immunity

• DOI: 10.1128/jvi.05949-11
• Publication Date: 2011-12-08T05:10:07Z
• Authors: Jens Eberlein; Bennett Davenport; Tom T. Nguyen; Francisco Victorino; Tim Sparwasser; Dirk Homann
• Keywords: CD4-Positive T-Lymphocytes; Male; Mice, Knockout; 0301 basic medicine; CD8-Positive T-Lymphocytes; Lymphocytic Choriomeningitis; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; CD28 Antigens; T-Lymphocyte Subsets; B7-1 Antigen; Animals; Humans; Lymphocytic choriomeningitis virus; Female; B7-2 Antigen; Immunologic Memory; Cells, Cultured

ABSTRACTThe lymphocytic choriomeningitis virus (LCMV) system constitutes one of the most widely used models for the study of infectious disease and the regulation of virus-specific T cell immunity. However, with respect to the activity of costimulatory and associated regulatory pathways, LCMV-specific T cell responses have long been regarded as relatively independent and thus distinct from the regulation of T cell immunity directed against many other viral pathogens. Here, we have reevaluated the contribution of CD28-CD80/86 costimulation in the LCMV system by use of CD80/86-deficient mice, and our results demonstrate that a disruption of CD28-CD80/86 signaling compromises the magnitude, phenotype, and/or functionality of LCMV-specific CD8+and/or CD4+T cell populations in all stages of the T cell response. Notably, a profound inhibition of secondary T cell immunity in LCMV-immune CD80/86-deficient mice emerged as a composite of both defective memory T cell development and a specific requirement for CD80 but not CD86 in the recall response, while a related experimental scenario of CD28-dependent yet CD80/86-independent secondary CD8+T cell immunity suggests the existence of a CD28 ligand other than CD80/86. Furthermore, we provide evidence that regulatory T cells (TREGs), the homeostasis of which is altered in CD80/86−/−mice, contribute to restrained LCMV-specific CD8+T cell responses in the presence of CD80/86. Our observations can therefore provide a more coherent perspective on CD28-CD80/86 costimulation in antiviral T cell immunity that positions the LCMV system within a shared context of multiple defects that virus-specific T cells acquire in the absence of CD28-CD80/86 costimulation.