Fas (CD95) is of principal importance to normal functioning of the immune system, as evidenced by the marked dysregulation of autoreactive B cells and accompanying autoantibody formation that characterize Fas-deficient animals. The sensitivity of B cells to Fas-mediated apoptosis is regulated by specific receptor signaling, in which surface immunoglobulin engagement, and IL-4R engagement, produces a state of Fas resistance. Modulation of susceptibility to Fas killing suggests a system that protects B cells during critical interactions with FasL-bearing, activated T cells, but that can contribute to the survival of autoreactive B cells when activated inappropriately. The broad, long term objective of this work is to understand the role of inducible Fas-resistance in normal immune responses and in the genesis of autoimmunity. Three antiapoptotic gene products are implicated as proximate mediators for resistance to Fas killing:
F AIM, FLIP, and Bcl-xL. The specific goal of this work is to illuminate the capability of these molecules to enhance serological immune responses and to alter the behavior of autoreactive B cells, separate from any other collateral effects of sIg or IL-4R engagement. This will be accomplished through 4 specific aims. 1. Determine the FAIM-dependency of normal immune responses by constructing and evaluating FAIM-deficient (knock-out) mice. 2. Evaluate the level, timing, and cellular origin of upregulated FAIM, FLIP, and Bcl-XL expression in lymphoid tissue during in vivo immune responses. 3. Compare the relative potency of FAIM, FLIP, and Bcl-xL in producing Fas-resistance in primary B cells by retroviral transduction in vitro and in promoting normal immune responses in vivo by constructing mixed chimeras in which bone marrow donors overexpress anti-apoptotic molecules alone and together. 4. Test the influence of FAIM, FLIP, and Bcl-xL, on the behavior of autoreactive B cells in two well-defined models: a) Ig receptor transgenic mice expressing VH3H9 anti-dsDNA in which B cells normally fail to enter germinal centers but do so on a Fas-deficient background; and, b) doubly transgenic mice expressing anti-HEL BCR and soluble HEL in which B cells are normally short-lived and tolerant but break tolerance in the presence of IL-4, B7.2, or Fas-deficiency. The results of these studies will test the hypothesis that inducible Fas-resistance promotes normal immune responses, and the hypothesis that aberrant Fas-resistance contributes to a breakdown in autoreactive B cell tolerance, and will thereby enhance understanding of both immunization strategy and the origin of autoimmunity.
| Kaku, Hiroaki; Cheng, Kai Fan; Al-Abed, Yousef et al. (2014) A novel mechanism of B cell-mediated immune suppression through CD73 expression and adenosine production. J Immunol 193:5904-13 |
| Kaku, Hiroaki; Rothstein, Thomas L (2009) Fas apoptosis inhibitory molecule enhances CD40 signaling in B cells and augments the plasma cell compartment. J Immunol 183:1667-74 |
| Kaku, Hiroaki; Rothstein, Thomas L (2009) Fas apoptosis inhibitory molecule expression in B cells is regulated through IRF4 in a feed-forward mechanism. J Immunol 183:5575-81 |
| Barrington, Robert A; Schneider, Thomas J; Pitcher, Lisa A et al. (2009) Uncoupling CD21 and CD19 of the B-cell coreceptor. Proc Natl Acad Sci U S A 106:14490-5 |
| Guo, Benchang; Tumang, Joseph R; Rothstein, Thomas L (2009) B cell receptor crosstalk: B cells express osteopontin through the combined action of the alternate and classical BCR signaling pathways. Mol Immunol 46:587-91 |
