The role of coronin 1 during cell mediated immune responses

Coronin 1 is one of 7 mammalian isoforms member of the evolutionary conserved WD40-repeat proteins that are involved in a variety of activities such a cell migration and cytokinesis. Coronin 1 is predominantly expressed in cells of hematopoietic origin, and it is the most conserved coronin isoform. Analysis of mice lacking coronin 1 revealed coronin 1 as a crucial pro-survival factor for peripheral T lymphocytes. It was found that coronin 1 was essential for Ca2+ mobilization upon T cell receptor (TCR) triggering; in the absence of coronin 1, T cell signaling does not result in Ca2+ mobilization thereby causing a rapid clearance of the T cells through apoptosis. Nevertheless, coronin 1-deficient mice are capable to mount specific antibody responses after immunization, although somewhat delayed for T cell dependent antigens. Together these results suggest an important role for coronin 1 in T cell signaling and in naïve T cell homeostasis.
Here, we investigate the cellular immune response to Murine cytomegalovirus (MCMV), Lympocytic choriomeningitis virus (LCMV) and Vesicular stomatitis virus (VSV), whose clearance and control are either dependent on CD8+ T cells or on CD4+ T cells, in wild type and coronin 1-deficient mice. Our results show surprisingly normal antiviral CD8+ T cell responses concerning magnitude, kinetics and functionality of virus specific CD8+ T cells. In contrast, virus specific CD4+ T cell responses were significantly impaired leading to loss of viral control in VSV infection. These findings suggest a more important role of coronin 1 for CD4+ T cell survival, activation and homeostatic proliferation in the periphery than for CD8+ T cells.
In the second part of that thesis we investigate the Natural killer (NK) cell immune response in the absence of coronin 1. Delay in viral control can be due to impaired NK cell response in the absence of coronin 1, which is believed to interact with Phospholipase C ? (PLC?) activity. Hence, NK cell receptor signaling share some similarities with TCR signaling. We analyzed the functionality of coronin 1-deficient NK cells after VSV infection, stimulation of NK cells with antibodies, YAC-1 tumor cell or Concanavalin A (Con A). We show that NK cell activation and functionality was not impaired in the absence of coronin 1. However, ConA treatment (in vivo and ex vivo) was associated with impaired Interferon ? (IFN?) production and cytotoxicity against YAC-1 cells. We found that coronin 1-deficiency was associated with increased sensitivity of NK cells leading to increased apoptosis rather than impaired NK cell activation upon Con A treatment.
Overall, our results suggest that coronin 1 is crucial for peripheral CD4+ T cell homeostasis and functionality but is largely dispensable for NK cell and CD8+ T cell mediated antiviral immunity.