Cell Death in the Maintenance and Abrogation of Tolerance: The Five Ws of Dying Cells  Thomas S. Griffith, Thomas A. Ferguson  Immunity  Volume 35, Issue 4, Pages 456-466 (October 2011) DOI: 10.1016/j.immuni.2011.08.011 Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 1 Proposed Mechanism of Tolerance or Immunity Induced by Naive or Activated Apoptotic T Cells Left: Induction of tolerance by naive apoptotic T cells. Naive apoptotic T cells are taken up by DCs, which remain in an immature state. The antigens derived from these apoptotic T cells are cross-presented on MHC class I to CD8+ T cells in the absence of costimulatory molecules and CD4+ T cell help. These “helpless” CD8+ T cells upregulate TRAIL expression and then go on to suppress subsequent immune responses mediated by CD4+ T cells. Right: Induction of immunity by activated apoptotic T cells. CD154-expressing, activated apoptotic T cells activate DCs to upregulate costimulatory molecules (CD80, CD86) and produce proinflammatory cytokines such as IL-12. Antigens derived from the activated apoptotic T cells are cross-presented on MHC class I and directly presented on MHC class II on matured DCs, resulting in the priming of both CD8+ and CD4+ T cells. Consequently, the proinflammatory cytokines and CD4+ T cell help the CD8+ T cells to fully differentiate into effector CTL instead of a helpless, TRAIL-expressing, CD8+ Treg cells. Immunity 2011 35, 456-466DOI: (10.1016/j.immuni.2011.08.011) Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 2 Predicting the Immunological Outcome via the Five Ws Each petal represents one of the five Ws and contains some of the factors considered in this review. The color gradient indicates a spectrum from tolerogenic (blue) to immunogenic (red). It is important to note that any element in a particular petal may be linked to any element in the other petals, resulting in a very large number of potential permutations. For example, a resting (when) lymphocyte (who) induced to die during sepsis (why) releases IL-10 (what) and is then engulfed by a splenic CD8α+ DC (where) and will induce immune tolerance via a helpless CD8+ T cell that makes TRAIL (how). Also consider another example: an apoptotic (when) normal tissue cell (who) infected with a virus (why) releases reduced HMGB1 (what) as it dies. The infected apoptotic cell is then engulfed by a CD8α+ DC in the skin (where), leading to cross-priming and activation of virus-specific CTL-mediated immunity (how). Immunity 2011 35, 456-466DOI: (10.1016/j.immuni.2011.08.011) Copyright © 2011 Elsevier Inc. Terms and Conditions