| Naive CD8+ T cells circulate throughout lymphoid tissues in order to sample peptide antigen that is derived from either self-proteins or potentially pathogenic foreign sources. T cells undergo a complex developmental selection process in order to specifically recognize a vast number of possible foreign peptide antigens and distinguish these from host-derived proteins. The precursor frequency of CD8+ T cells that are specific to a given epitope is estimated to be ∼100--200 cells out of ∼2--4 x 107 total CD8+ T cells per mouse. Massive expansion of CD8+ T cells that recognize foreign antigen is therefore essential to resolve intracellular microbial infections, and can reach ∼1 x 105-fold increases in cell number in particular cases. CD8+ T cells must also localize to the site of infection to perform their primary function of killing infected cells. In order to characterize several important stages of an antiviral T cell response, we have undertaken a comprehensive study of the CD8 + T cell response to respiratory influenza virus infection of mice, using two complementary experimental models. Using a TCR transgenic CD8 + T cell adoptive transfer model, we have identified important features of the early CD8+ T cell response to influenza virus, encompassing activation, differentiation, proliferation, and migration. These include the dynamic expression of key cell surface proteins, sites and kinetics of T cell proliferation, acquisition of effector molecule expression, and migration to the infected lung and peripheral lymphoid tissues. We have also used a nontransgenic model to primarily detail later aspects of the CD8+ T cell response to influenza virus infection, such as the frequency and magnitude of virus-specific CD8+ T cells in the infected lungs, as well as the phenotypes of antiviral CD8+ T cells persisting in the lungs in the memory phase after resolution of infection. We demonstrate that a high proportion of virus-specific CD8+ T cells are present in infected mouse lungs, which are directed nearly exclusively to four virus-derived peptide antigens. We also show that high frequencies of effector molecule-positive T cells are present in the lungs before they are scored by conventional antigen-specific means of detection. |
