T Cell Cosignaling Molecules in Transplantation Mandy L. Ford  Immunity  Volume 44, Issue 5, Pages 1020-1033 (May 2016) DOI: 10.1016/j.immuni.2016.04.012 Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 1 Mechanisms of Belatacept-Resistant Rejection following Transplantation Belatacept, a CTLA-4-Ig fusion protein, binds to CD80 and CD86 thereby inhibiting CD28-mediated signaling during the initiation of a donor-reactive T cell response. Mechanisms by which alloreactive T cell responses still occur in the presence of belatacept, precipitating allograft rejection, include the following: (1) Foxp3+ Treg cell function might be diminished due to the inability of CTLA-4 expressed on the Treg cell to ligate CD80 and CD86 in the presence of belatacept; (2) CD28− CD4+ or CD8+ T cells that arise as a result of increasing age or chronic inflammation might be inherently independent of CD28-mediated costimulation during activation; and (3) Th17 cells express increased levels of CTLA-4 and are highly sensitive to CTLA-4-mediated coinhibitory signals, rendering them more activated when CTLA-4 ligation of CD80 and CD86 is blocked by belatacept. Immunity 2016 44, 1020-1033DOI: (10.1016/j.immuni.2016.04.012) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 2 Costimulatory and Coinhibitory Molecule Interactions of the CD28 Family CD28 family members commonly have more than one ligand, and interactions include cross-talk between costimulatory and coinhibitory receptors. Dotted lines represent interactions between CD28 family members expressed on T cells and APCs, resulting in either costimulatory (+) or coinhibitory (–) signaling into T cells. Immunity 2016 44, 1020-1033DOI: (10.1016/j.immuni.2016.04.012) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 3 Cellular Interactions Involving the CD154-CD40 Pathway Classic T cell licensing involves CD154 expressed on activated CD4+ T cells ligating CD40 expressed on DC or other APC, resulting in transmission of an activating signal into the APC (red arrows represent directionality of signaling). CD154-CD40 interactions can also occur through ligation of CD154+ CD4+ T cells by CD40-expressing CD8+ T cells. There is potentially also a role for CD154 expressed on the surface of a CD11c+ DC, binding to CD40 on the surface of an activated CD8+ T cell. Finally, CD154 expressed on CD4+ T cells can also interact with CD11b+ monocytes or macrophages. Immunity 2016 44, 1020-1033DOI: (10.1016/j.immuni.2016.04.012) Copyright © 2016 Elsevier Inc. Terms and Conditions