Novel aspects of the T cell response to lymphopenia and to Listeria infection

We have investigated two essential qualities of the T cell, namely their ability to respond to depletion by dividing and their ability to respond to cytokines during infection. The process by which the immune system senses a decrease in its T cell numbers and triggers division is unknown. This homeostatic proliferation of naive T cells requires MHC-peptide contact and cytokines. The requirement for MHC-peptide implies that T cells of identical specificity might compete for these complexes during homeostatic proliferation, but this had not been demonstrated. In the first part of this thesis, we have described the ability of T cells of the same clonal specificity to compete during the repopulation of lymphopenic environments. Clonal T cell populations inhibit the division of T cells of their own clonotype but not T cells of differing peptide specificity. We also investigated the role of commensal bacteria in this process. We find that acute homeostatic proliferation is reduced in germ-free SCID mice. A subset of fast-proliferating cells, the main component of proliferation in genetically deficient but not irradiated mice, is particularly affected by the presence of commensal bacteria. These cells may represent activated T cells responding to commensal bacteria. Finally, we have investigated the role of type I IFN in the T cell response to intracellular infection. We describe T cell responses to the bacterium Listeria monocytogenes (LM) in mice lacking the receptor for type I IFN. Type I IFN is an important early cytokine in viral infection with effects on both innate and adaptive immunity. Although type I IFN is produced during bacterial infection, the effect on this cytokine on the T cell response to LM was unknown. Despite early reductions in activation of both T cells and DCs, we found few differences in the antigen-specific T cell response to LM in the absence of type I IFN signaling. Memory T cells specific for a LCMV epitope were produced by infection of knockout mice with recombinant LM but failed to resolve LCMV infection upon challenge. This failure highlights an unexpected role for type I IFN during memory T cell responses.