T Cell Cosignaling Molecules in Transplantation

Abstract

The ultimate outcome of alloreactivity versus tolerance following transplantation is potently influenced by the constellation of cosignaling molecules expressed by immune cells during priming with alloantigen, and the net sum of costimulatory and coinhibitory signals transmitted via ligation of these molecules. Intense investigation over the last two decades has yielded a detailed understanding of the kinetics, cellular distribution, and intracellular signaling networks of cosignaling molecules such as the CD28, TNF, and TIM families of receptors in alloimmunity. More recent work has better defined the cellular and molecular mechanisms by which engagement of cosignaling networks serve to either dampen or augment alloimmunity. These findings will likely aid in the rational development of novel immunomodulatory strategies to prolong graft survival and improve outcomes following transplantation.

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: 1) Foxp3⁺ Treg cell function may 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 may 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.

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.

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.