Myocarditis is an inflammation of the myocardium which often follows microbial infections. Enteroviruses (picornaviruses) and adenoviruses are most frequently implicated in clinical disease. We have developed a murine model of coxsackievirus B3 (CVB3) myocarditis. Pathogenicity requires virus induction of a strong antigen-specific CD4+Th1 (IFN+) cell response while conditions which promote a CD4+Th2 (IL-4+) response prevent myocarditis. T cells expressing the V4 T cell receptor are crucial to generation of CD4+Th1 immunity. It is well accepted that innate effectors such as + cells modulate adaptive immune responses. The accepted mechanisms for this modulation depend upon cytokine release by the innate effectors which provides an environmental milieu favorable to a specific Th response;and innate effector impact on antigen presenting cells resulting in changes in accessory molecule or cytokine expression by the antigen presenting cells leading to alterations in CD4+ cell responses. To the best of our knowledge, we are the only laboratory hypothesizing that + cells directly bind to CD4+ cells modulating the Th phenotype. We have shown that + cells selectively kill CD4+Th2 cells leaving the CD4+Th1 cells intact. Currently, nearly all studies show that CD4+Th1 cells are selectively susceptible to Fas-dependent apoptosis while CD4+Th2 cells are remarkably resistant. Our data is diametrically opposite of accepted knowledge. The major question is why in our CVB3 model, CD4+Th2 cells are apoptosis susceptible and how much the selective elimination of Th2 cells by + cells contributes to the CD4+Th1 dominance in CVB3 infected mice. We hypothesize that there would be differences in CD1d, Fas or anti-apoptotic factors, such as c-FLIPL, between CD4+ Th1 and Th2 cells and that these differences allow the selective killing of the Th2 cells. Elimination of effector CD4+ cells at the end of antigenic stimulation conserves resources and space in the hemopoietic compartment, but immune contraction should apply to both CD4+Th1 and Th2 cells. Contraction of only CD4+Th1 cells could allow progressive accumulation of CD4+Th2 and ultimate imbalance of the immune system. Innate effectors such as + cells may play an important role in eliminating activated CD4+Th2 cells. The question central to this proposal is how innate effectors distinguish between Th1 and Th2 cells, killing the latter but not the former.
The Specific Aims are: 1) Determine if + cells are only required for activating CD4+ cells or for maintaining the activated cells in vivo;(2) Determine if CD1d expression on CD4+ cells is required for + cell immunomodulation of the CD4+ response in vivo and the role of IFN production by V4+ cells;(3) Determine whether CD1d or Fas expression on CD4+ Th1 or Th2 cell clones differs and explains the increased susceptibility of Th2 clones to V4+ cell induced apoptosis.;and (4) Determine if c-FLIPL expression differs between CD4+Th1 and Th2 cells and elevated levels in Th1 cells protects them from V4+ cell mediated killing. .
This grant will investigate the role of Vgamma4+ T cells in selectively killing activated CD4+Th2 cells by Fas-dependent mechanisms, as a method for immune contraction after an immune response.
The Specific Aims are to 1) Determine if + cells are only required for activating CD4+ cells or for maintaining the activated cells in vivo. 2) Determine if Fas or CD1d expression on CD4+ cells is required for + cell immunomodulation of the CD4+ response in vivo and the role of IFN production by V4+ cells. 3) Determine whether CD1d or Fas expression on CD4+ Th1 or Th2 cell clones differs and explains the increased susceptibility of Th2 clones to V4+ cell induced apoptosis. 4) Determine if c-FLIPL expression differs between CD4+Th1 and Th2 cells and whether elevated levels in Th1 cells protects them from V4+ cell mediated killing.
|Buskiewicz, Iwona A; Koenig, Andreas; Roberts, Brian et al. (2014) c-FLIP-Short reduces type I interferon production and increases viremia with coxsackievirus B3. PLoS One 9:e96156|
|Liu, Wei; Moussawi, Mohamad; Roberts, Brian et al. (2013) Cross-regulation of T regulatory-cell response after coxsackievirus B3 infection by NKT and ?? T cells in the mouse. Am J Pathol 183:441-9|
|Liu, Wei; Dienz, Oliver; Roberts, Brian et al. (2012) IL-21R expression on CD8+ T cells promotes CD8+ T cell activation in coxsackievirus B3 induced myocarditis. Exp Mol Pathol 92:327-33|