Disruption of Coronin 1 Signaling in T Cells Promotes Allograft Tolerance while Maintaining Anti-Pathogen Immunity

The ability of the immune system to discriminate self from non-self is essential for eradicating microbial pathogens but is also responsible for allograft rejection. Whether it is possible to selectively suppress alloresponses while maintaining anti-pathogen immunity remains unknown. We found that mice deficient in coronin 1, a regulator of naive T cell homeostasis, fully retained allografts while maintaining T cell-specific responses against microbial pathogens. Mechanistically, coronin 1-deficiency increased cyclic adenosine monophosphate (cAMP) concentrations to suppress allo-specific T cell responses. Costimulation induced on microbe-infected antigen presenting cells was able to overcome cAMP-mediated immunosuppression to maintain anti-pathogen immunity. In vivo pharmacological modulation of this pathway or a prior transfer of coronin 1-deficient T cells actively suppressed allograft rejection. These results define a coronin 1-dependent regulatory axis in T cells important for allograft rejection and suggest that modulation of this pathway may be a promising approach to achieve long-term acceptance of mismatched allografts

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

Role for coronin 1 in mouse NK cell function

Coronin 1, a member of the evolutionary conserved WD repeat protein family of coronin proteins is expressed in all leukocytes, but a role for coronin 1 in natural killer (NK) cell homeostasis and function remains unclear. Here, we have analyzed the number and functionality of NK cells in the presence and absence of coronin 1. In coronin 1-deficient mice, absolute NK cell numbers and phenotype were comparable to wild type mice in blood, spleen and liver. Following in vitro stimulation of the activating NK cell receptors NK1.1, NKp46, Ly49D and NKG2D, coronin 1-deficient NK cells were functional with respect to interferon-γ production, degranulation and intracellular Ca(2+) mobilization. Also, both wild type as well as coronin 1-deficient NK cells showed comparable cytotoxic activity. Furthermore, activation and functionality of NK cells following Vesicular Stomatitis Virus (VSV) infection was similar between wild type and coronin 1-deficient mice. Taken together these data suggest that coronin 1 is dispensable for mouse NK cell homeostasis and function

Diverging role for coronin 1 in antiviral CD4(+) and CD8(+) T cell responses

Coronin 1 is a member of the evolutionary conserved WD repeat protein family and is highly expressed in hematopoietic cells. Coronin 1 is essential for Ca(2+) mobilization upon T cell receptor (TCR) stimulation providing a pro-survival signal for naïve peripheral T cells. Both in mouse and in human, coronin 1 deficiency is associated with severe T cell lymphopenia. In this work, we have analyzed antiviral T cell-mediated immunity in the presence and absence of coronin 1 in vivo after infection with lymphocytic choriomenigitis virus (LCMV) and vesicular stomatitis virus (VSV) in mice. Despite low peripheral T cell numbers we found that LCMV-specific CD8(+) T cell responses were normal in the absence of coronin 1 and kinetics of LCMV-clearance were similar compared to wild type mice. In contrast, CD4(+) T cell responses were profoundly decreased after LCMV- and VSV-infection. We propose that coronin 1 plays a differential role in CD8(+) versus CD4(+) T cell responses and activation